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  • Functional mosaic organization of neuroligins in neuronal circuits
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-20
    Liming Qin, Sile Guo, Ying Han, Xiankun Wang, Bo Zhang

    Abstract Complex brain circuitry with feedforward and feedback systems regulates neuronal activity, enabling neural networks to process and drive the entire spectrum of cognitive, behavioral, sensory, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits is underpinned by hundreds of synaptic adhesion molecules that span synaptic junctions. Dysfunction of a single molecule or molecular interaction at synapses can lead to disrupted circuit activity and brain disorders. Neuroligins, a family of cell adhesion molecules, were first identified as postsynaptic-binding partners of presynaptic neurexins and are essential for synapse specification and maturation. Here, we review recent advances in our understanding of how this family of adhesion molecules controls neuronal circuit assembly by acting in a synapse-specific manner.

  • Revisiting cellular immune response to oncogenic Marek’s disease virus: the rising of avian T-cell immunity
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-20
    Yi Yang, Maoli Dong, Xiaoli Hao, Aijian Qin, Shaobin Shang

    Abstract Marek’s disease virus (MDV) is a highly oncogenic alphaherpesvirus that causes deadly T-cell lymphomas and serves as a natural virus-induced tumor model in chickens. Although Marek’s disease (MD) is well controlled by current vaccines, the evolution of MDV field viruses towards increasing virulence is concerning as a better vaccine to combat very virulent plus MDV is still lacking. Our understanding of molecular and cellular immunity to MDV and its immunopathogenesis has significantly improved, but those findings about cellular immunity to MDV are largely out-of-date, hampering the development of more effective vaccines against MD. T-cell-mediated cellular immunity was thought to be of paramount importance against MDV. However, MDV also infects macrophages, B cells and T cells, leading to immunosuppression and T-cell lymphoma. Additionally, there is limited information about how uninfected immune cells respond to MDV infection or vaccination, specifically, the mechanisms by which T cells are activated and recognize MDV antigens and how the function and properties of activated T cells correlate with immune protection against MDV or MD tumor. The current review revisits the roles of each immune cell subset and its effector mechanisms in the host immune response to MDV infection or vaccination from the point of view of comparative immunology. We particularly emphasize areas of research requiring further investigation and provide useful information for rational design and development of novel MDV vaccines.

  • Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-19
    T. E. Thingholm, L. Rönnstrand, P. A. Rosenberg

    Abstract Zinc is required for the regulation of proliferation, metabolism, and cell signaling. It is an intracellular second messenger, and the cellular level of ionic, mobile zinc is strictly controlled by zinc transporters. In mammals, zinc homeostasis is primarily regulated by ZIP and ZnT zinc transporters. The importance of these transporters is underscored by the list of diseases resulting from changes in transporter expression and activity. However, despite numerous structural studies of the transporters revealing both zinc binding sites and motifs important for transporter function, the exact molecular mechanisms regulating ZIP and ZnT activities are still not clear. For example, protein phosphorylation was found to regulate ZIP7 activity resulting in the release of Zn2+ from intracellular stores leading to phosphorylation of tyrosine kinases and activation of signaling pathways. In addition, sequence analyses predict all 24 human zinc transporters to be phosphorylated suggesting that protein phosphorylation is important for regulation of transporter function. This review describes how zinc transporters are implicated in a number of important human diseases. It summarizes the current knowledge regarding ZIP and ZnT transporter structures and points to how protein phosphorylation seems to be important for the regulation of zinc transporter activity. The review addresses the need to investigate the role of protein phosphorylation in zinc transporter function and regulation, and argues for a pressing need to introduce quantitative phosphoproteomics to specifically target zinc transporters and proteins involved in zinc signaling. Finally, different quantitative phosphoproteomic strategies are suggested.

  • Reductive stress in striated muscle cells
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-18
    Ilaria Bellezza, Francesca Riuzzi, Sara Chiappalupi, Cataldo Arcuri, Ileana Giambanco, Guglielmo Sorci, Rosario Donato

    Abstract Reductive stress is defined as a condition of sustained increase in cellular glutathione/glutathione disulfide and NADH/NAD+ ratios. Reductive stress is emerging as an important pathophysiological event in several diseased states, being as detrimental as is oxidative stress. Occurrence of reductive stress has been documented in several cardiomyopathies and is an important pathophysiological factor particularly in coronary artery disease and myocardial infarction. Excess activation of the transcription factor, Nrf2—the master regulator of the antioxidant response—, consequent in most cases to defective autophagy, can lead to reductive stress. In addition, hyperglycemia-induced activation of the polyol pathway can lead to increased NADH/NAD+ ratio, which might translate into increased levels of hydrogen sulfide—via enhanced activity of cystathionine β-synthase—that would fuel reductive stress through inhibition of mitochondrial complex I. Reductive stress may be either a potential weapon against cancer priming tumor cells to apoptosis or a cancer’s ally promoting tumor cell proliferation and making tumor cells resistant to reactive oxygen species-inducing drugs. In non-cancer pathological states reductive stress is definitely harmful paradoxically leading to reactive oxygen species overproduction via excess NADPH oxidase 4 activity. In face of the documented occurrence of reductive stress in several heart diseases, there is much less information about the occurrence and effects of reductive stress in skeletal muscle tissue. In the present review we describe relevant results emerged from studies of reductive stress in the heart and review skeletal muscle conditions in which reductive stress has been experimentally documented and those in which reductive stress might have an as yet unrecognized pathophysiological role. Establishing whether reductive stress has a (patho)physiological role in skeletal muscle will hopefully contribute to answer the question whether antioxidant supplementation to the general population, athletes, and a large cohort of patients (e.g. heart, sarcopenic, dystrophic, myopathic, cancer, and bronco-pulmonary patients) is harmless or detrimental.

  • Targets for protection and mitigation of radiation injury
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-18
    Ehsan khodamoradi, Mojtaba Hoseini-Ghahfarokhi, Peyman Amini, Elahe Motevaseli, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, Masoud Najafi, Bagher Farhood

    Abstract Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.

  • The Rab5 activator RME-6 is required for amyloid precursor protein endocytosis depending on the YTSI motif
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-17
    Simone Eggert, Tomas Gruebl, Ritu Rajender, Carsten Rupp, Bianca Sander, Amelie Heesch, Marius Zimmermann, Sebastian Hoepfner, Hanswalter Zentgraf, Stefan Kins

    Abstract Endocytosis of the amyloid precursor protein (APP) is critical for generation of β-amyloid, aggregating in Alzheimer's disease. APP endocytosis depending on the intracellular NPTY motif is well investigated, whereas involvement of the YTSI (also termed BaSS) motif remains controversial. Here, we show that APP lacking the YTSI motif (ΔYTSI) displays reduced localization to early endosomes and decreased internalization rates, similar to APP ΔNPTY. Additionally, we show that the YTSI-binding protein, PAT1a interacts with the Rab5 activator RME-6, as shown by several independent assays. Interestingly, knockdown of RME-6 decreased APP endocytosis, whereas overexpression increased the same. Similarly, APP ΔNPTY endocytosis was affected by PAT1a and RME-6 overexpression, whereas APP ΔYTSI internalization remained unchanged. Moreover, we could show that RME-6 mediated increase of APP endocytosis can be diminished upon knocking down PAT1a. Together, our data identify RME-6 as a novel player in APP endocytosis, involving the YTSI-binding protein PAT1a.

  • Prohibitin ligands: a growing armamentarium to tackle cancers, osteoporosis, inflammatory, cardiac and neurological diseases
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-15
    Dong Wang, Redouane Tabti, Sabria Elderwish, Hussein Abou-Hamdan, Amel Djehal, Peng Yu, Hajime Yurugi, Krishnaraj Rajalingam, Canan G. Nebigil, Laurent Désaubry

    Abstract Over the last three decades, the scaffold proteins prohibitins-1 and -2 (PHB1/2) have emerged as key signaling proteins regulating a myriad of signaling pathways in health and diseases. Small molecules targeting PHBs display promising effects against cancers, osteoporosis, inflammatory, cardiac and neurodegenerative diseases. This review provides an updated overview of the various classes of PHB ligands, with an emphasis on their mechanism of action and therapeutic potential. We also describe how these ligands have been used to explore PHB signaling in different physiological and pathological settings.

  • Founder cells for hepatocytes during liver regeneration: from identification to application
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-14
    Saisai Wei, Jiacheng Tang, Xiujun Cai

    Abstract Liver regeneration (LR) capacity in vertebrates developed through natural selection over a hundred million years of evolution. To maintain homeostasis or recover from various injuries, liver cells must regenerate; this process includes the renewal of parenchymal and nonparenchymal cells as well as the formation of liver structures. The cellular origin of newly grown tissue is one of the critical questions in this area and has been a subject of prolonged debate. The regenerative tissue may derive from either hepatocyte self-duplication or liver stem/progenitor cells (LSPCs). Recently, hepatocyte subpopulations and cholangiocytes were also described as important founder cells. The niche that triggers the proliferation of hepatocytes and the differentiation of LSPCs has been extensively studied. Meanwhile, in vitro culture systems for liver founder cells and organoids have been developed rapidly for mechanistic studies and potential therapeutic purposes. This review summarizes the cellular sources and niches that give rise to renewed hepatocytes during LR, and it also describes in vitro culture studies of those founder cells for future applications, as well as current reports for stem cell-based therapies for liver diseases.

  • Physiological functions of SPP/SPPL intramembrane proteases
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-12
    Torben Mentrup, Florencia Cabrera-Cabrera, Regina Fluhrer, Bernd Schröder

    Abstract Intramembrane proteolysis describes the cleavage of substrate proteins within their hydrophobic transmembrane segments. Several families of intramembrane proteases have been identified including the aspartyl proteases Signal peptide peptidase (SPP) and its homologues, the SPP-like (SPPL) proteases SPPL2a, SPPL2b, SPPL2c and SPPL3. As presenilin homologues, they employ a similar catalytic mechanism as the well-studied γ-secretase. However, SPP/SPPL proteases cleave transmembrane proteins with a type II topology. The characterisation of SPP/SPPL-deficient mouse models has highlighted a still growing spectrum of biological functions and also promoted the substrate discovery of these proteases. In this review, we will summarise the current hypotheses how phenotypes of these mouse models are linked to the molecular function of the enzymes. At the cellular level, SPP/SPPL-mediated cleavage events rather provide specific regulatory switches than unspecific bulk proteolysis. By this means, a plethora of different cell biological pathways is influenced including signal transduction, membrane trafficking and protein glycosylation.

  • Prevalence and significance of the commonest phosphorylated motifs in the human proteome: a global analysis
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-12
    Luca Cesaro, Lorenzo A. Pinna

    Abstract Protein phosphorylation is the most frequent post-translational modification by which the properties of eukaryotic proteins can be reversibly modified. In humans, over 500 protein kinases generate a huge phosphoproteome including more than 200,000 individual phosphosites, a figure which is still continuously increasing. The in vivo selectivity of protein kinases is the outcome of a multifaceted and finely tuned process where numerous factors play an integrated role. To gain information about the actual contribution to this process of local features that reflect the interaction of the protein targets with the catalytic site of the kinases, the prevalence of the commonest motifs determining the consensus sequence of Ser/Thr-specific kinases has been examined in the whole human phosphoproteome and in the phosphoproteomes generated by a panel of the 47 most pleiotropic protein kinases. Our analysis shows that: (1) most phosphosites do conform to at least one of the motifs considered, with a substantial proportion conforming to two or more of them; (2) some motifs, with special reference to the one recognized by protein kinase CK2 (pS/pT-x-x-E/D) are very promiscuous, being abundantly represented also at the phosphosites of all the other protein kinases considered; (3) by contrast, other phosphorylated motifs, notably pS/pT-P, pS/pT-Q and pS-x-E, are more discriminatory and selective, being nearly absent in the phosphosites that are not attributable to certain categories of kinases. The information provided will prove helpful to make reliable inferences based on the manual inspection of individual phosphosites.

  • Dynamics of kinetochore structure and its regulations during mitotic progression
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-12
    Masatoshi Hara, Tatsuo Fukagawa

    Abstract Faithful chromosome segregation during mitosis in eukaryotes requires attachment of the kinetochore, a large protein complex assembled on the centromere of each chromosome, to the spindle microtubules. The kinetochore is a structural interface for the microtubule attachment and provides molecular surveillance mechanisms that monitor and ensure the precise microtubule attachment as well, including error correction and spindle assembly checkpoint. During mitotic progression, the kinetochore undergoes dynamic morphological changes that are observable through electron microscopy as well as through fluorescence microscopy. These structural changes might be associated with the kinetochore function. In this review, we summarize how the dynamics of kinetochore morphology are associated with its functions and discuss recent findings on the switching of protein interaction networks in the kinetochore during cell cycle progression.

  • Abnormal X chromosome inactivation and tumor development
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-10
    Dan Wang, Le Tang, Yingfen Wu, Chunmei Fan, Shanshan Zhang, Bo Xiang, Ming Zhou, Xiaoling Li, Yong Li, Guiyuan Li, Wei Xiong, Zhaoyang Zeng, Can Guo

    Abstract During embryonic development, one of the two X chromosomes of a mammalian female cell is randomly inactivated by the X chromosome inactivation mechanism, which is mainly dependent on the regulation of the non-coding RNA X-inactive specific transcript at the X chromosome inactivation center. There are three proteins that are essential for X-inactive specific transcript to function properly: scaffold attachment factor-A, lamin B receptor, and SMRT- and HDAC-associated repressor protein. In addition, the absence of X-inactive specific transcript expression promotes tumor development. During the process of chromosome inactivation, some tumor suppressor genes escape inactivation of the X chromosome and thereby continue to play a role in tumor suppression. A well-functioning tumor suppressor gene on the idle X chromosome in women is one of the reasons they have a lower propensity to develop cancer than men, women thereby benefit from this enhanced tumor suppression. This review will explore the mechanism of X chromosome inactivation, discuss the relationship between X chromosome inactivation and tumorigenesis, and consider the consequent sex differences in cancer.

  • Beta-arrestins operate an on/off control switch for focal adhesion kinase activity
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-10
    Revu Ann Alexander, Isaure Lot, Kusumika Saha, Guillaume Abadie, Mireille Lambert, Eleonore Decosta, Hiroyuki Kobayashi, Alexandre Beautrait, Aurélie Borrull, Atef Asnacios, Michel Bouvier, Mark G. H. Scott, Stefano Marullo, Hervé Enslen

    Abstract Focal adhesion kinase (FAK) regulates key biological processes downstream of G protein-coupled receptors (GPCRs) in normal and cancer cells, but the modes of kinase activation by these receptors remain unclear. We report that after GPCR stimulation, FAK activation is controlled by a sequence of events depending on the scaffolding proteins β-arrestins and G proteins. Depletion of β-arrestins results in a marked increase in FAK autophosphorylation and focal adhesion number. We demonstrate that β-arrestins interact directly with FAK and inhibit its autophosphorylation in resting cells. Both FAK–β-arrestin interaction and FAK inhibition require the FERM domain of FAK. Following the stimulation of the angiotensin receptor AT1AR and subsequent translocation of the FAK–β-arrestin complex to the plasma membrane, β-arrestin interaction with the adaptor AP-2 releases inactive FAK from the inhibitory complex, allowing its activation by receptor-stimulated G proteins and activation of downstream FAK effectors. Release and activation of FAK in response to angiotensin are prevented by an AP-2-binding deficient β-arrestin and by a specific inhibitor of β-arrestin/AP-2 interaction; this inhibitor also prevents FAK activation in response to vasopressin. This previously unrecognized mechanism of FAK regulation involving a dual role of β-arrestins, which inhibit FAK in resting cells while driving its activation at the plasma membrane by GPCR-stimulated G proteins, opens new potential therapeutic perspectives in cancers with up-regulated FAK.

  • Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-07
    Balázs A. Györffy, Vilmos Tóth, György Török, Péter Gulyássy, Réka Á. Kovács, Henrietta Vadászi, András Micsonai, Melinda E. Tóth, Miklós Sántha, László Homolya, László Drahos, Gábor Juhász, Katalin A. Kékesi, József Kardos

    Abstract Synaptic functional disturbances with concomitant synapse loss represent central pathological hallmarks of Alzheimer’s disease. Excessive accumulation of cytotoxic amyloid oligomers is widely recognized as a key event that underlies neurodegeneration. Certain complement components are crucial instruments of widespread synapse loss because they can tag synapses with functional impairments leading to their engulfment by microglia. However, an exact understanding of the affected synaptic functions that predispose to complement-mediated synapse elimination is lacking. Therefore, we conducted systematic proteomic examinations on synaptosomes prepared from an amyloidogenic mouse model of Alzheimer’s disease (APP/PS1). Synaptic fractions were separated according to the presence of the C1q-tag using fluorescence-activated synaptosome sorting and subjected to proteomic comparisons. The results raised the decline of mitochondrial functions in the C1q-tagged synapses of APP/PS1 mice based on enrichment analyses, which was verified using flow cytometry. Additionally, proteomics results revealed extensive alterations in the level of septin protein family members, which are known to dynamically form highly organized pre- and postsynaptic supramolecular structures, thereby affecting synaptic transmission. High-resolution microscopy investigations demonstrated that synapses with considerable amounts of septin-3 and septin-5 show increased accumulation of C1q in APP/PS1 mice compared to the wild-type ones. Moreover, a strong positive correlation was apparent between synaptic septin-3 levels and C1q deposition as revealed via flow cytometry and confocal microscopy examinations. In sum, our results imply that deterioration of synaptic mitochondrial functions and alterations in the organization of synaptic septins are associated with complement-dependent synapse loss in Alzheimer’s disease.

  • A cyclin-dependent kinase, CDK11/p58, represses cap-dependent translation during mitosis
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-06
    Sihyeon An, Oh Sung Kwon, Jinbae Yu, Sung Key Jang

    Abstract During mitosis, translation of most mRNAs is strongly repressed; none of the several explanatory hypotheses suggested can fully explain the molecular basis of this phenomenon. Here we report that cyclin-dependent CDK11/p58—a serine/threonine kinase abundantly expressed during M phase—represses overall translation by phosphorylating a subunit (eIF3F) of the translation factor eIF3 complex that is essential for translation initiation of most mRNAs. Ectopic expression of CDK11/p58 strongly repressed cap-dependent translation, and knockdown of CDK11/p58 nullified the translational repression during M phase. We identified the phosphorylation sites in eIF3F responsible for M phase-specific translational repression by CDK11/p58. Alanine substitutions of CDK11/p58 target sites in eIF3F nullified its effects on cell cycle-dependent translational regulation. The mechanism of translational regulation by the M phase-specific kinase, CDK11/p58, has deep evolutionary roots considering the conservation of CDK11 and its target sites on eIF3F from C. elegans to humans.

  • Misfolded amyloid-β-42 impairs the endosomal–lysosomal pathway
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-05
    Karen E. Marshall, Devkee M. Vadukul, Kevin Staras, Louise C. Serpell

    Abstract Misfolding and aggregation of proteins is strongly linked to several neurodegenerative diseases, but how such species bring about their cytotoxic actions remains poorly understood. Here we used specifically-designed optical reporter probes and live fluorescence imaging in primary hippocampal neurons to characterise the mechanism by which prefibrillar, oligomeric forms of the Alzheimer’s-associated peptide, Aβ42, exert their detrimental effects. We used a pH-sensitive reporter, Aβ42-CypHer, to track Aβ internalisation in real-time, demonstrating that oligomers are rapidly taken up into cells in a dynamin-dependent manner, and trafficked via the endo-lysosomal pathway resulting in accumulation in lysosomes. In contrast, a non-assembling variant of Aβ42 (vAβ42) assayed in the same way is not internalised. Tracking ovalbumin uptake into cells using CypHer or Alexa Fluor tags shows that preincubation with Aβ42 disrupts protein uptake. Our results identify a potential mechanism by which amyloidogenic aggregates impair cellular function through disruption of the endosomal–lysosomal pathway.

  • CX3CR1 positively regulates BCR signaling coupled with cell metabolism via negatively controlling actin remodeling
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-04
    Na Li, Panpan Jiang, Anwei Chen, Xi Luo, Yukai Jing, Lu Yang, Danqing Kang, Qiuyue Chen, Ju Liu, Jiang Chang, Julia Jellusova, Heather Miller, Lisa Westerberg, Cong-Yi Wang, Quan Gong, Chaohong Liu

    Abstract As an important chemokine receptor, the role of CX3CR1 has been studied extensively on the migration of lymphocytes including T and B cells. Although CX3CR1+ B cells have immune suppressor properties, little is known about its role on the regulation of BCR signaling and B cell differentiation as well as the underlying molecular mechanism. We have used CX3CR1 KO mice to study the effect of CX3CR1 deficiency on BCR signaling and B cell differentiation. Interestingly, we found that proximal BCR signaling, such as the activation of CD19, BTK and SHIP was reduced in CX3CR1 KO B cells upon antigenic stimulation. However, the activation of mTORC signaling was enhanced. Mechanistically, we found that the reduced BCR signaling in CX3CR1 KO B cells was due to reduced BCR clustering, which is caused by the enhanced actin accumulation by the plasma membrane via increased activation of WASP. This caused an increased differentiation of MZ B cells in CX3CR1 KO mice and an enhanced generation of plasma cells (PC) and antibodies. Our study shows that CX3CR1 regulates BCR signaling via actin remodeling and affects B cell differentiation and the humoral immune response.

  • Functional and transcriptomic analyses of the NF-Y family provide insights into the defense mechanisms of honeybees under adverse circumstances
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-03
    Guilin Li, Hang Zhao, Hongbin Guo, Ying Wang, Xuepei Cui, Baohua Xu, Xingqi Guo

    Abstract As predominant pollinators, honeybees are important for crop production and terrestrial ecosystems. Recently, various environmental stresses have led to large declines in honeybee populations in many regions. The ability of honeybees to respond to these stresses is critical for their survival. However, the details of the stress defense mechanisms of honeybees have remained elusive. Here, we found that the Nuclear Factor Y (NF-Y) family (containing NF-YA, NF-YB, and NF-YC) is a novel stress mediator family that regulates honeybee environmental stress resistance. NF-YA localized in the nucleus, NF-YB accumulated in the cytoplasm, and NF-YC presented in both the nucleus and cytoplasm. NF-YC interacted with NF-YA and NF-YB in vitro and in vivo, and the nuclear import of NF-YB relied on its interaction with NF-YC. We further found that the expression of NF-Y was induced under multiple stress conditions. In addition, NF-Y regulated many stress responses and antioxidant genes at the transcriptome-wide level, and knockdown of NF-Y repressed the expression of stress-inducible genes, particularly LOC108003540 and LOC107994062, under adverse circumstances. Silencing NF-Y lowered honeybee stress resistance by reducing total antioxidant capacity and enhancing oxidative impairment. Collectively, these results indicate that NF-Y plays important roles in stress responses. Our study sheds light on the underlying defense mechanisms of honeybees under environmental stress.

  • Endosymbiosis before eukaryotes: mitochondrial establishment in protoeukaryotes
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-01
    István Zachar, Gergely Boza

    Abstract Endosymbiosis and organellogenesis are virtually unknown among prokaryotes. The single presumed example is the endosymbiogenetic origin of mitochondria, which is hidden behind the event horizon of the last eukaryotic common ancestor. While eukaryotes are monophyletic, it is unlikely that during billions of years, there were no other prokaryote–prokaryote endosymbioses as symbiosis is extremely common among prokaryotes, e.g., in biofilms. Therefore, it is even more precarious to draw conclusions about potentially existing (or once existing) prokaryotic endosymbioses based on a single example. It is yet unknown if the bacterial endosymbiont was captured by a prokaryote or by a (proto-)eukaryote, and if the process of internalization was parasitic infection, slow engulfment, or phagocytosis. In this review, we accordingly explore multiple mechanisms and processes that could drive the evolution of unicellular microbial symbioses with a special attention to prokaryote–prokaryote interactions and to the mitochondrion, possibly the single prokaryotic endosymbiosis that turned out to be a major evolutionary transition. We investigate the ecology and evolutionary stability of inter-species microbial interactions based on dependence, physical proximity, cost–benefit budget, and the types of benefits, investments, and controls. We identify challenges that had to be conquered for the mitochondrial host to establish a stable eukaryotic lineage. Any assumption about the initial interaction of the mitochondrial ancestor and its contemporary host based solely on their modern relationship is rather perilous. As a result, we warn against assuming an initial mutually beneficial interaction based on modern mitochondria–host cooperation. This assumption is twice fallacious: (i) endosymbioses are known to evolve from exploitative interactions and (ii) cooperativity does not necessarily lead to stable mutualism. We point out that the lack of evidence so far on the evolution of endosymbiosis from mutual syntrophy supports the idea that mitochondria emerged from an exploitative (parasitic or phagotrophic) interaction rather than from syntrophy.

  • Thalidomide targets EGFL6 to inhibit EGFL6/PAX6 axis-driven angiogenesis in small bowel vascular malformation
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-01
    Chao-Tao Tang, Qing-Wei Zhang, Shan Wu, Ming-Yu Tang, Qian Liang, Xiao-Lu Lin, Yun-Jie Gao, Zhi-Zheng Ge

    Abstract Background Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide. Methods We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN. Results The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide. Conclusion Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.

  • EMT signaling: potential contribution of CRISPR/Cas gene editing
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-01
    Reza Mohammadinejad, Alessio Biagioni, Ganesan Arunkumar, Rebecca Shapiro, Kun-Che Chang, Mohammed Sedeeq, Aftab Taiyab, Mohammad Hashemabadi, Abbas Pardakhty, Ali Mandegary, Jean-Paul Thiery, Amir Reza Aref, Iman Azimi

    Abstract Epithelial to mesenchymal transition (EMT) is a complex plastic and reversible cellular process that has critical roles in diverse physiological and pathological phenomena. EMT is involved in embryonic development, organogenesis and tissue repair, as well as in fibrosis, cancer metastasis and drug resistance. In recent years, the ability to edit the genome using the clustered regularly interspaced palindromic repeats (CRISPR) and associated protein (Cas) system has greatly contributed to identify or validate critical genes in pathway signaling. This review delineates the complex EMT networks and discusses recent studies that have used CRISPR/Cas technology to further advance our understanding of the EMT process.

  • Epigenetic regulation of centromere function
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-02-01
    Charmaine Yan Yu Wong, Bernard Chi Hang Lee, Karen Wing Yee Yuen

    Abstract The centromere is a specialized region on the chromosome that directs equal chromosome segregation. Centromeres are usually not defined by DNA sequences alone. How centromere formation and function are determined by epigenetics is still not fully understood. Active centromeres are often marked by the presence of centromeric-specific histone H3 variant, centromere protein A (CENP-A). How CENP-A is assembled into the centromeric chromatin during the cell cycle and propagated to the next cell cycle or the next generation to maintain the centromere function has been intensively investigated. In this review, we summarize current understanding of how post-translational modifications of CENP-A and other centromere proteins, centromeric and pericentric histone modifications, non-coding transcription and transcripts contribute to centromere function, and discuss their intricate relationships and potential feedback mechanisms.

  • Clinical application of immune checkpoints in targeted immunotherapy of prostate cancer
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-31
    Sevda Jafari, Ommoleila Molavi, Houman Kahroba, Mohammad Saied Hejazi, Nasrin Maleki-Dizaji, Siamak Barghi, Seyed Hossein Kiaie, Farhad Jadidi-Niaragh

    Abstract Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4+ and CD8+), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa.

  • The neuroscience of sugars in taste, gut-reward, feeding circuits, and obesity
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-31
    Ranier Gutierrez, Esmeralda Fonseca, Sidney A. Simon

    Abstract Throughout the animal kingdom sucrose is one of the most palatable and preferred tastants. From an evolutionary perspective, this is not surprising as it is a primary source of energy. However, its overconsumption can result in obesity and an associated cornucopia of maladies, including type 2 diabetes and cardiovascular disease. Here we describe three physiological levels of processing sucrose that are involved in the decision to ingest it: the tongue, gut, and brain. The first section describes the peripheral cellular and molecular mechanisms of sweet taste identification that project to higher brain centers. We argue that stimulation of the tongue with sucrose triggers the formation of three distinct pathways that convey sensory attributes about its quality, palatability, and intensity that results in a perception of sweet taste. We also discuss the coding of sucrose throughout the gustatory pathway. The second section reviews how sucrose, and other palatable foods, interact with the gut–brain axis either through the hepatoportal system and/or vagal pathways in a manner that encodes both the rewarding and of nutritional value of foods. The third section reviews the homeostatic, hedonic, and aversive brain circuits involved in the control of food intake. Finally, we discuss evidence that overconsumption of sugars (or high fat diets) blunts taste perception, the post-ingestive nutritional reward value, and the circuits that control feeding in a manner that can lead to the development of obesity.

  • Infection and atherosclerosis: TLR-dependent pathways
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-30
    Bowei Li, Yuanpeng Xia, Bo Hu

    Abstract Atherosclerotic vascular disease (ASVD) is a chronic process, with a progressive course over many years, but it can cause acute clinical events, including acute coronary syndromes (ACS), myocardial infarction (MI) and stroke. In addition to a series of typical risk factors for atherosclerosis, like hyperlipidemia, hypertension, smoking and obesity, emerging evidence suggests that atherosclerosis is a chronic inflammatory disease, suggesting that chronic infection plays an important role in the development of atherosclerosis. Toll-like receptors (TLRs) are the most characteristic members of pattern recognition receptors (PRRs), which play an important role in innate immune mechanism. TLRs play different roles in different stages of infection of atherosclerosis-related pathogens such as Chlamydia pneumoniae (C. pneumoniae), periodontal pathogens including Porphyromonas gingivalis (P. gingivalis), Helicobacter pylori (H. pylori) and human immunodeficiency virus (HIV). Overall, activation of TLR2 and 4 seems to have a profound impact on infection-related atherosclerosis. This article reviews the role of TLRs in the process of atherosclerosis after C. pneumoniae and other infections and the current status of treatment, with a view to providing a new direction and potential therapeutic targets for the study of ASVD.

  • Adenosine-to-inosine RNA editing in the immune system: friend or foe?
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-29
    Taisuke Nakahama, Yukio Kawahara

    Abstract Our body expresses sensors to detect pathogens through the recognition of expressed molecules, including nucleic acids, lipids, and proteins, while immune tolerance prevents an overreaction with self and the development of autoimmune disease. Adenosine (A)-to-inosine (I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a post-transcriptional modification that can potentially occur at over 100 million sites in the human genome, mainly in Alu repetitive elements that preferentially form a double-stranded RNA (dsRNA) structure. A-to-I conversion within dsRNA, which may induce a structural change, is required to escape from the host immune system, given that endogenous dsRNAs transcribed from Alu repetitive elements are potentially recognized by melanoma differentiation-associated protein 5 (MDA5) as non-self. Of note, loss-of-function mutations in the ADAR1 gene cause Aicardi–Goutières syndrome, a congenital autoimmune disease characterized by encephalopathy and a type I interferon (IFN) signature. However, the loss of ADAR1 in cancer cells with an IFN signature induces lethality via the activation of protein kinase R in addition to MDA5. This makes cells more sensitive to immunotherapy, highlighting the opposing immune status of autoimmune diseases (overreaction) and cancer (tolerance). In this review, we provide an overview of insights into two opposing aspects of RNA editing that functions as a modulator of the immune system in autoimmune diseases and cancer.

  • Light entrainment of retinal biorhythms: cryptochrome 2 as candidate photoreceptor in mammals
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-25
    Jacques Vanderstraeten, Philippe Gailly, E. Pascal Malkemper

    Abstract The mechanisms that synchronize the biorhythms of the mammalian retina with the light/dark cycle are independent of those synchronizing the rhythms in the central pacemaker, the suprachiasmatic nucleus. The identity of the photoreceptor(s) responsible for the light entrainment of the retina of mammals is still a matter of debate, and recent studies have reported contradictory results in this respect. Here, we suggest that cryptochromes (CRY), in particular CRY 2, are involved in that light entrainment. CRY are highly conserved proteins that are a key component of the cellular circadian clock machinery. In plants and insects, they are responsible for the light entrainment of these biorhythms, mediated by the light response of their flavin cofactor (FAD). In mammals, however, no light-dependent role is currently assumed for CRY in light-exposed tissues, including the retina. It has been reported that FAD influences the function of mammalian CRY 2 and that human CRY 2 responds to light in Drosophila, suggesting that mammalian CRY 2 keeps the ability to respond to light. Here, we hypothesize that CRY 2 plays a role in the light entrainment of retinal biorhythms, at least in diurnal mammals. Indeed, published data shows that the light intensity dependence and the wavelength sensitivity commonly reported for that light entrainment fits the light sensitivity and absorption spectrum of light-responsive CRY. We propose experiments to test our hypothesis and to further explore the still-pending question of the function of CRY 2 in the mammalian retina.

  • The lung microbiota: role in maintaining pulmonary immune homeostasis and its implications in cancer development and therapy
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-23
    Michele Sommariva, Valentino Le Noci, Francesca Bianchi, Simone Camelliti, Andrea Balsari, Elda Tagliabue, Lucia Sfondrini

    Abstract Like other body districts, lungs present a complex bacteria community. An emerging function of lung microbiota is to promote and maintain a state of immune tolerance, to prevent uncontrolled and not desirable inflammatory response caused by inhalation of harmless environmental stimuli. This effect is mediated by a continuous dialog between commensal bacteria and immune cells resident in lungs, which express a repertoire of sensors able to detect microorganisms. The same receptors are also involved in the recognition of pathogens and in mounting a proper immune response. Due to its important role in preserving lung homeostasis, the lung microbiota can be also considered a mirror of lung health status. Indeed, several studies indicate that lung bacterial composition drastically changes during the occurrence of pulmonary pathologies, such as lung cancer, and the available data suggest that the modifications of lung microbiota can be part of the etiology of tumors in lungs and can influence their progression and response to therapy. These results provide the scientific rationale to analyze lung microbiota composition as biomarker for lung cancer and to consider lung microbiota a new potential target for therapeutic intervention to reprogram the antitumor immune microenvironment. In the present review, we discussed about the role of lung microbiota in lung physiology and summarized the most relevant data about the relationship between lung microbiota and cancer.

  • A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-23
    Cláudia Almeida Loureiro, Francisco R. Pinto, Patrícia Barros, Paulo Matos, Peter Jordan

    Abstract Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the recessive genetic disease cystic fibrosis, where the chloride transport across the apical membrane of epithelial cells mediated by the CFTR protein is impaired. CFTR protein trafficking to the plasma membrane (PM) is the result of a complex interplay between the secretory and membrane recycling pathways that control the number of channels present at the membrane. In addition, the ion transport activity of CFTR at the PM is modulated through post-translational protein modifications. Previously we described that spleen tyrosine kinase (SYK) phosphorylates a specific tyrosine residue in the nucleotide-binding domain 1 domain and this modification can regulate the PM abundance of CFTR. Here we identified the underlying biochemical mechanism using peptide pull-down assays followed by mass spectrometry. We identified in bronchial epithelial cells that the adaptor protein SHC1 recognizes tyrosine-phosphorylated CFTR through its phosphotyrosine-binding domain and that the formation of a complex between SHC1 and CFTR is induced at the PM in the presence of activated SYK. The depletion of endogenous SHC1 expression was sufficient to promote an increase in CFTR at the PM of these cells. The results identify a SYK/SHC1 pathway that regulates the PM levels of CFTR channels, contributing to a better understanding of how CFTR-mediated chloride secretion is regulated.

  • The mechanisms of pathological extramedullary hematopoiesis in diseases
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-23
    Xinxin Yang, Degao Chen, Haixia Long, Bo Zhu

    Abstract Extramedullary hematopoiesis (EMH) is the expansion and differentiation of hematopoietic stem and progenitor cells outside of the bone marrow. In postnatal life, as a compensatory mechanism for ineffective hematopoiesis of the bone marrow, pathological EMH is triggered by hematopoietic disorders, insufficient hematopoietic compensation, and other pathological stress conditions, such as infection, advanced tumors, anemia, and metabolic stress. Pathological EMH has been reported in many organs, and the sites of pathological EMH may be related to reactivation of the embryonic hematopoietic structure in these organs. As a double-edged sword (blood and immune cell supplementation as well as clinical complications), pathological EMH has been widely studied in recent years. In particular, pathological EMH induced by late-stage tumors contributes to tumor immunosuppression. Thus, a deeper understanding of the mechanism of pathological EMH may be conducive to the development of therapies against the pathological processes that induce EMH. This article reviews the recent progress of research on the cellular and molecular mechanisms of pathological EMH in specific diseases.

  • Biomedical applications of electrical stimulation
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-23
    Siwei Zhao, Abijeet Singh Mehta, Min Zhao

    Abstract This review provides a comprehensive overview on the biomedical applications of electrical stimulation (EStim). EStim has a wide range of direct effects on both biomolecules and cells. These effects have been exploited to facilitate proliferation and functional development of engineered tissue constructs for regenerative medicine applications. They have also been tested or used in clinics for pain mitigation, muscle rehabilitation, the treatment of motor/consciousness disorders, wound healing, and drug delivery. However, the research on fundamental mechanism of cellular response to EStim has fell behind its applications, which has hindered the full exploitation of the clinical potential of EStim. Moreover, despite the positive outcome from the in vitro and animal studies testing the efficacy of EStim, existing clinical trials failed to establish strong, conclusive supports for the therapeutic efficacy of EStim for most of the clinical applications mentioned above. Two potential directions of future research to improve the clinical utility of EStim are presented, including the optimization and standardization of the stimulation protocol and the development of more tissue-matching devices.

  • The effect of fornix deep brain stimulation in brain diseases
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 

    Abstract Deep brain stimulation is used to alleviate symptoms of neurological and psychiatric disorders including Parkinson’s disease, epilepsy, and obsessive–compulsive-disorder. Electrically stimulating limbic structures has been of great interest, and in particular, the region of the fornix. We conducted a systematic search for studies that reported clinical and preclinical outcomes of deep brain stimulation within the fornix up to July 2019. We identified 13 studies (7 clinical, 6 preclinical) that examined the effects of fornix stimulation in Alzheimer’s disease (n = 9), traumatic brain injury (n = 2), Rett syndrome (n = 1), and temporal lobe epilepsy (n = 1). Overall, fornix stimulation can lead to decreased rates of cognitive decline (in humans), enhanced memory (in humans and animals), visuo-spatial memorization (in humans and animals), and improving verbal recollection (in humans). While the exact mechanisms of action are not completely understood, studies suggest fornix DBS to be involved with increased functional connectivity and neurotransmitter levels, as well as enhanced neuroplasticity.

  • Melatonin inhibits Warburg-dependent cancer by redirecting glucose oxidation to the mitochondria: a mechanistic hypothesis
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-22
    Russel J. Reiter, Ramaswamy Sharma, Qiang Ma, Sergio Rorsales-Corral, Luiz G. de Almeida Chuffa

    Abstract Melatonin has the ability to intervene in the initiation, progression and metastasis of some experimental cancers. A large variety of potential mechanisms have been advanced to describe the metabolic and molecular events associated with melatonin’s interactions with cancer cells. There is one metabolic perturbation that is common to a large number of solid tumors and accounts for the ability of cancer cells to actively proliferate, avoid apoptosis, and readily metastasize, i.e., they use cytosolic aerobic glycolysis (the Warburg effect) to rapidly generate the necessary ATP required for the high metabolic demands of the cancer cells. There are several drugs, referred to as glycolytic agents, that cause cancer cells to abandon aerobic glycolysis and shift to the more conventional mitochondrial oxidative phosphorylation for ATP synthesis as in normal cells. In doing so, glycolytic agents also inhibit cancer growth. Herein, we hypothesize that melatonin also functions as an inhibitor of cytosolic glycolysis in cancer cells using mechanisms, i.e., downregulation of the enzyme (pyruvate dehydrogenase kinase) that interferes with the conversion of pyruvate to acetyl CoA in the mitochondria, as do other glycolytic drugs. In doing so, melatonin halts the proliferative activity of cancer cells, reduces their metastatic potential and causes them to more readily undergo apoptosis. This hypothesis is discussed in relation to the previously published reports. Whereas melatonin is synthesized in the mitochondria of normal cells, we hypothesize that this synthetic capability is not present in cancer cell mitochondria because of the depressed acetyl CoA; acetyl CoA is necessary for the rate limiting enzyme in melatonin synthesis, arylalkylamine-N-acetyltransferase. Finally, the ability of melatonin to switch glucose oxidation from the cytosol to the mitochondria also explains how tumors that become resistant to conventional chemotherapies are re-sensitized to the same treatment when melatonin is applied.

  • Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-21
    Xing-Liang Fan, Yuelin Zhang, Xin Li, Qing-Ling Fu

    Abstract Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell–cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies.

  • PEBP1/RKIP behavior: a mirror of actin-membrane organization
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-20
    Françoise Schoentgen, Slavica Jonic

    Abstract Phosphatidylethanolamine-binding protein 1 (PEBP1), a small 21 kDa protein, is implicated in several key processes of the living cell. The deregulation of PEBP1, especially its downregulation, leads to major diseases such as cancer and Alzheimer’s disease. PEBP1 was found to interact with numerous proteins, especially kinases and GTPases, generally inhibiting their activity. To understand the basic functionality of this amazing small protein, we have considered several known processes that it modulates and we have discussed the role of each molecular target in these processes. Here, we propose that cortical actin organization, associated with membrane changes, is involved in the majority of the processes modulated by PEBP1. Furthermore, based on recent data, we summarize some key PEBP1-interacting proteins, and we report their respective functions and focus on their relationships with actin organization. We suggest that, depending on the cell status and environment, PEBP1 is an organizer of the actin-membrane composite material.

  • Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-20
    Stefan Schäbler, Kelechi M. Amatobi, Melanie Horn, Dirk Rieger, Charlotte Helfrich-Förster, Martin J. Mueller, Christian Wegener, Agnes Fekete

    Abstract The fruit fly Drosophila is a prime model in circadian research, but still little is known about its circadian regulation of metabolism. Daily rhythmicity in levels of several metabolites has been found, but knowledge about hydrophobic metabolites is limited. We here compared metabolite levels including lipids between period01 (per01) clock mutants and Canton-S wildtype (WTCS) flies in an isogenic and non-isogenic background using LC–MS. In the non-isogenic background, metabolites with differing levels comprised essential amino acids, kynurenines, pterinates, glycero(phospho)lipids, and fatty acid esters. Notably, detectable diacylglycerols (DAG) and acylcarnitines (AC), involved in lipid metabolism, showed lower levels in per01 mutants. Most of these differences disappeared in the isogenic background, yet the level differences for AC as well as DAG were consistent for fly bodies. AC levels were dependent on the time of day in WTCS in phase with food consumption under LD conditions, while DAGs showed weak daily oscillations. Two short-chain ACs continued to cycle even in constant darkness. per01 mutants in LD showed no or very weak diel AC oscillations out of phase with feeding activity. The low levels of DAGs and ACs in per01 did not correlate with lower total food consumption, body mass or weight. Clock mutant flies showed higher sensitivity to starvation independent of their background-dependent activity level. Our results suggest that neither feeding, energy storage nor mobilisation is significantly affected in per01 mutants, but point towards impaired mitochondrial activity, supported by upregulation of the mitochondrial stress marker 4EBP in the clock mutants.

  • Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha (sAPPα)
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-20
    Nawab John Dar, Gordon W. Glazner

    Abstract Amyloid precursor protein (APP) is a transmembrane protein expressed largely within the central nervous system. Upon cleavage, it does not produce the toxic amyloid peptide (Aβ) only, which is involved in neurodegenerative progressions but via a non-amyloidogenic pathway it is metabolized to produce a soluble fragment (sAPPα) through α-secretase. While a lot of studies are focusing on the role played by APP in the pathogenesis of Alzheimer’s disease, sAPPα is reported to have numerous neuroprotective effects and it is being suggested as a candidate with possible therapeutic potential against Alzheimer’s disease. However, the mechanisms through which sAPPα precisely works remain elusive. We have presented a comprehensive review of how sAPPα is regulating the neuroprotective effects in different biological models. Moreover, we have focused on the role of sAPPα during different developmental stages of the brain, neurogenic microenvironment in the brain and how this metabolite of APP is regulating the neurogenesis which is regarded as a compelling approach to ameliorate the impaired learning and memory deficits in dementia and diseases like Alzheimer’s disease. sAPPα exerts beneficial physiological, biochemical and behavioral effects mitigating the detrimental effects of neurotoxic compounds. It has shown to increase the proliferation rate of numerous cell types and promised the synaptogenesis, neurite outgrowth, cell survival and cell adhesion. Taken together, we believe that further studies are warranted to investigate the exact mechanism of action so that sAPPα could be developed as a novel therapeutic target against neuronal deficits.

  • Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-18
    Alexandra Wetzel, Bettina Scholtka, Christian Gerecke, Burkhard Kleuser

    Abstract Ulcerative colitis (UC) is characterized by relapsing–remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and anti-inflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNFα or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3−/−). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3−/−. In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.

  • Regulation of spermatogenesis and reproductive capacity by Igf3 in tilapia
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-18
    Minghui Li, Xingyong Liu, Shengfei Dai, Hesheng Xiao, Shuangshuang Qi, Yibing Li, Qiaoyuan Zheng, Mimi Jie, Christopher H. K. Cheng, Deshou Wang

    Abstract A novel insulin-like growth factor (igf3), which is exclusively expressed in the gonads, has been widely identified in fish species. Recent studies have indicated that Igf3 regulates spermatogonia proliferation and differentiation in zebrafish; however, detailed information on the role of this Igf needs further in vivo investigation. Here, using Nile tilapia (Oreochromis niloticus) as an animal model, we report that igf3 is required for spermatogenesis and reproduction. Knockout of igf3 by CRISPR/Cas9 severely inhibited spermatogonial proliferation and differentiation at 90 days after hatching, the time critical for meiosis initiation, and resulted in less spermatocytes in the mutants. Although spermatogenesis continued to occur later, more spermatocytes and less spermatids were observed in the igf3−/− testes when compared with wild type of testes at adults, indicating that Igf3 regulates spermatocyte to spermatid transition. Importantly, a significantly increased occurrence of apoptosis in spermatids was observed after loss of Igf3. Therefore, igf3−/− males were subfertile with drastically reduced semen volume and sperm count. Conversely, the overexpression of Igf3 in XY tilapia enhanced spermatogenesis leading to more spermatids and sperm count. Transcriptomic analysis revealed that the absence of Igf3 resulted in dysregulation of many genes involved in cell cycle, meiosis and pluripotency regulators that are critical for spermatogenesis. In addition, in vitro gonadal culture with 17α-methyltetosterone (MT) and 11-ketotestosterone (11-KT) administration and in vivo knockout of cyp11c1 demonstrated that igf3 expression is regulated by androgens, suggesting that Igf3 acts downstream of androgens in fish spermatogenesis. Notably, the igf3 knockout did not affect body growth, indicating that this Igf specifically functions in reproduction. Taken together, our data provide genetic evidence for fish igf3 in the regulation of reproductive capacity by controlling spermatogenesis.

  • Systems biology: current status and challenges
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-13
    Anze Zupanic, Hans C. Bernstein, Ines Heiland

    Abstract We put together a special issue on current approaches in systems biology with a focus on mathematical modeling of metabolic networks. Mathematical models have increasingly been used to unravel molecular mechanisms of complex dynamic biological processes. We here provide a short introduction into the topics covered in this special issue, highlighting current developments and challenges.

  • DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-13
    Senad Medunjanin, Maximilian Putzier, Till Nöthen, Sönke Weinert, Thilo Kähne, Blerim Luani, Werner Zuschratter, Ruediger C. Braun-Dullaeus

    Abstract The transcription factors of the nuclear factor κB (NF-κB) family play a pivotal role in the cellular response to DNA damage. Genotoxic stress-induced activation of NF-κB differs from the classical canonical pathway by shuttling of the NF-κB Essential Modifier (IKKγ/NEMO) subunit through the nucleus. Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR). Blockade of DNA-PK by a specific shRNA or by DNA-PKcs-deficient cells abrogated NEMO entry into the nucleus, as well. Accordingly, SUMOylation of NEMO, a prerequisite of nuclear NEMO, was abolished. Based on these observations, we propose a model in which NEMO phosphorylation by DNA-PK provides the first step in the nucleocytoplasmic trafficking of NEMO.

  • GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-11
    Rocío Vila-Bedmar, Marta Cruces-Sande, Alba C. Arcones, Hanneke L. D. M. Willemen, Patricia Prieto, Isabel Moreno-Indias, Daniel Díaz-Rodríguez, Sara Francisco, Rafael I. Jaén, Carolina Gutiérrez-Repiso, Cobi J. Heijnen, Lisardo Boscá, Manuel Fresno, Annemieke Kavelaars, Federico Mayor, Cristina Murga

    Abstract Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2+/− mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2+/− mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations.

  • The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-10
    Inmaculada Ruz-Maldonado, Bo Liu, Patricio Atanes, Attilio Pingitore, Guo Cai Huang, Pratik Choudhary, Shanta J. Persaud

    Abstract Aims Endocannabinoids are lipid mediators involved in the regulation of glucose homeostasis. They interact with the canonical cannabinoid receptors CB1 and CB2, and it is now apparent that some cannabinoid receptor ligands are also agonists at GPR55. Thus, CB1 antagonists such as SR141716A, also known as rimonabant, and AM251 act as GPR55 agonists in some cell types. The complex pharmacological properties of cannabinoids make it difficult to fully identify the relative importance of CB1 and GPR55 in the functional effects of SR141716A, and AM251. Here, we determine whether SR141716A and AM251 regulation of mouse and human islet function is through their action as GPR55 agonists. Methods Islets isolated from Gpr55+/+ and Gpr55−/− mice and human donors were incubated in the absence or presence of 10 µM SR141716A or AM251, concentrations that are known to activate GPR55. Insulin secretion, cAMP, IP1, apoptosis and β-cell proliferation were quantified by standard techniques. Results Our results provide the first evidence that SR141716A and AM251 are not GPR55 agonists in islets, as their effects are maintained in islets isolated from Gpr55−/− mice. Their signalling through Gq-coupled cascades to induce insulin secretion and human β-cell proliferation, and protect against apoptosis in vitro, indicate that they have direct beneficial effects on islet function. Conclusion These observations may be useful in directing development of peripherally restricted novel therapeutics that are structurally related to SR141716A and AM251, and which potentiate glucose-induced insulin secretion and stimulate β-cell proliferation.

  • Correction to: Molecular mechanism of olesoxime-mediated neuroprotection through targeting α-synuclein interaction with mitochondrial VDAC
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-09
    Amandine Rovini, Philip A. Gurnev, Alexandra Beilina, María Queralt-Martín, William Rosencrans, Mark R. Cookson, Sergey M. Bezrukov, Tatiana K. Rostovtseva

    In the published article, an error was noticed and this has been corrected with this erratum publication.

  • Correction to: Tet3 regulates cellular identity and DNA methylation in neural progenitor cells
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-09
    Mafalda Santiago, Claudia Antunes, Marta Guedes, Michelina Iacovino, Michael Kyba, Wolf Reik, Nuno Sousa, Luísa Pinto, Miguel R. Branco, C. Joana Marques

    The article Tet3 regulates cellular identity and DNA methylation in neural progenitor cells, written by Miguel R. Branco and C. Joana Marques, was originally published electronically on the publisher’s internet portal.

  • Retraction Note to: cGMP-phosphodiesterase 6, transducin and Wnt5a/Frizzled-2-signaling control cGMP and Ca 2+ homeostasis in melanoma cells
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-09
    Alexandr V. Bazhin, Vojtech Tambor, Boyan Dikov, Pavel P. Philippov, Dirk Schadendorf, Stefan B. Eichmüller

    The Editor-in-Chief has retracted this article [1] due to errors in Figs. 1b, c and 4.

  • Biased agonists at the human Y 1 receptor lead to prolonged membrane residency and extended receptor G protein interaction
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-09
    Anette Kaiser, Lizzy Wanka, Isabelle Ziffert, Annette G. Beck-Sickinger

    Abstract Functionally selective ligands to address specific cellular responses downstream of G protein-coupled receptors (GPCR) open up new possibilities for therapeutics. We designed and characterized novel subtype- and pathway-selective ligands. Substitution of position Q34 of neuropeptide Y to glycine (G34-NPY) results in unprecedented selectivity over all other YR subtypes. Moreover, this ligand displays a significant bias towards activation of the Gi/o pathway over recruitment of arrestin-3. Notably, no bias is observed for an established Y1R versus Y2R selective ligand carrying a proline at position 34 (F7,P34-NPY). Next, we investigated the spatio-temporal signaling at the Y1R and demonstrated that G protein-biased ligands promote a prolonged localization at the cell membrane, which leads to enhanced G protein signaling, while endosomal receptors do not contribute to cAMP signaling. Thus, spatial components are critical for the signaling of the Y1R that can be modulated by tailored ligands and represent a novel mode for biased pathways. Graphic abstract

  • Human pluripotent stem cell-derived chondroprogenitors for cartilage tissue engineering
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-08
    Naoki Nakayama, Azim Pothiawala, John Y. Lee, Nadine Matthias, Katsutsugu Umeda, Bryan K. Ang, Johnny Huard, Yun Huang, Deqiang Sun

    Abstract The cartilage of joints, such as meniscus and articular cartilage, is normally long lasting (i.e., permanent). However, once damaged, especially in large animals and humans, joint cartilage is not spontaneously repaired. Compensating the lack of repair activity by supplying cartilage-(re)forming cells, such as chondrocytes or mesenchymal stromal cells, or by transplanting a piece of normal cartilage, has been the basis of therapy for biological restoration of damaged joint cartilage. Unfortunately, current biological therapies face problems on a number of fronts. The joint cartilage is generated de novo from a specialized cell type, termed a ‘joint progenitor’ or ‘interzone cell’ during embryogenesis. Therefore, embryonic chondroprogenitors that mimic the property of joint progenitors might be the best type of cell for regenerating joint cartilage in the adult. Pluripotent stem cells (PSCs) are expected to differentiate in culture into any somatic cell type through processes that mimic embryogenesis, making human (h)PSCs a promising source of embryonic chondroprogenitors. The major research goals toward the clinical application of PSCs in joint cartilage regeneration are to (1) efficiently generate lineage-specific chondroprogenitors from hPSCs, (2) expand the chondroprogenitors to the number needed for therapy without loss of their chondrogenic activity, and (3) direct the in vivo or in vitro differentiation of the chondroprogenitors to articular or meniscal (i.e., permanent) chondrocytes rather than growth plate (i.e., transient) chondrocytes. This review is aimed at providing the current state of research toward meeting these goals. We also include our recent achievement of successful generation of “permanent-like” cartilage from long-term expandable, hPSC-derived ectomesenchymal chondroprogenitors.

  • Metabolic regulation of neurodifferentiation in the adult brain
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-07
    Camilla Maffezzini, Javier Calvo-Garrido, Anna Wredenberg, Christoph Freyer

    Understanding the mechanisms behind neurodifferentiation in adults will be an important milestone in our quest to identify treatment strategies for cognitive disorders observed during our natural ageing or disease. It is now clear that the maturation of neural stem cells to neurones, fully integrated into neuronal circuits requires a complete remodelling of cellular metabolism, including switching the cellular energy source. Mitochondria are central for this transition and are increasingly seen as the regulatory hub in defining neural stem cell fate and neurodevelopment. This review explores our current knowledge of metabolism during adult neurodifferentiation.

  • Dynein-mediated nuclear translocation of yes-associated protein through microtubule acetylation controls fibroblast activation
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-07
    Eunae You, Panseon Ko, Jangho Jeong, Seula Keum, Jung-Woong Kim, Young-Jin Seo, Woo Keun Song, Sangmyung Rhee

    Abstract Myofibroblasts are the major cell type that is responsible for increase in the mechanical stiffness in fibrotic tissues. It has well documented that the TGF-β/Smad axis is required for myofibroblast differentiation under the rigid substrate condition. However, the mechanism driving myofibroblast differentiation in soft substrates remains unknown. In this research, we demonstrated that interaction of yes-associated protein (YAP) and acetylated microtubule via dynein, a microtubule motor protein drives nuclear localization of YAP in the soft matrix, which in turn increased TGF-β1-induced transcriptional activity of Smad for myofibroblast differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear translocation of YAP and decreased the TGF-β1-induced Smad activity even though phosphorylation and nuclear localization of Smad occurred normally in α-tubulin acetyltransferase 1 (α-TAT1) knockout cell. Moreover, microtubule acetylation prominently appeared in the fibroblast-like cells nearby the blood vessel in the fibrotic liver induced by CCl4 administration, which was conversely decreased by TGF-β receptor inhibitor. As a result, quantitative inhibition of microtubule acetylation may be suggested as a new target for overcoming fibrotic diseases.

  • An intact keratin network is crucial for mechanical integrity and barrier function in keratinocyte cell sheets
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-07
    Susanne Karsch, Fanny Büchau, Thomas M. Magin, Andreas Janshoff

    The isotype-specific composition of the keratin cytoskeleton is important for strong adhesion, force resilience, and barrier function of the epidermis. However, the mechanisms by which keratins regulate these functions are still incompletely understood. In this study, the role and significance of the keratin network for mechanical integrity, force transmission, and barrier formation were analyzed in murine keratinocytes. Following the time-course of single-cell wound closure, wild-type (WT) cells slowly closed the gap in a collective fashion involving tightly connected neighboring cells. In contrast, the mechanical response of neighboring cells was compromised in keratin-deficient cells, causing an increased wound area initially and an inefficient overall wound closure. Furthermore, the loss of the keratin network led to impaired, fragmented cell–cell junctions, and triggered a profound change in the overall cellular actomyosin architecture. Electric cell-substrate impedance sensing of cell junctions revealed a dysfunctional barrier in knockout (Kty−/−) cells compared to WT cells. These findings demonstrate that Kty−/− cells display a novel phenotype characterized by loss of mechanocoupling and failure to form a functional barrier. Re-expression of K5/K14 rescued the barrier defect to a significant extent and reestablished the mechanocoupling with remaining discrepancies likely due to the low abundance of keratins in that setting. Our study reveals the major role of the keratin network for mechanical homeostasis and barrier functionality in keratinocyte layers.

  • Hypoxia: a barricade to conquer the pancreatic cancer
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-06
    Zhen Tan, Jin Xu, Bo Zhang, Si Shi, Xianjun Yu, Chen Liang

    Pancreatic cancer (PC) remains one of the most extremely lethal malignancies worldwide due to late diagnosis and early metastasis, with a 1-year overall survival rate of approximately 20%. The hypoxic microenvironment, induced by intratumoral hypoxia, promotes tumor invasion and progression, leading to chemotherapy or radiotherapy resistance and eventual mortality after treatment of PC. However, the role of the hypoxic microenvironment in PC is complicated and requires further investigation. In this article, we review recent advances regarding the regulation of malignant behaviors in PC, which provide insight into the potential of hypoxic microenvironment activation therapy for the therapeutic agents.

  • The role of lipocalin-2 in age-related macular degeneration (AMD)
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-04
    Sayan Ghosh, Nadezda Stepicheva, Meysam Yazdankhah, Peng Shang, Alan M. Watson, Stacey Hose, Haitao Liu, Joseph Weiss, J. Samuel Zigler, Mallika Valapala, Simon C. Watkins, Debasish Sinha

    Abstract Lipocalins are a family of secreted adipokines which play important roles in various biological processes. Lipocalin-2 (LCN-2) has been shown to be involved in acute and chronic inflammation. This particular protein is critical in the pathogenesis of several diseases including cancer, diabetes, obesity, and multiple sclerosis. Herein, we discuss the general molecular basis for the involvement of LCN-2 in acute infections and chronic disease progression and also ascertain the probable role of LCN-2 in ocular diseases, particularly in age-related macular degeneration (AMD). We elaborate on the signaling cascades which trigger LCN-2 upregulation in AMD and suggest therapeutic strategies for targeting such pathways.

  • Curse of the devil: molecular insights into the emergence of transmissible cancers in the Tasmanian devil ( Sarcophilus harrisii )
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-03
    Amanda L. Patchett, Andrew S. Flies, A. Bruce Lyons, Gregory M. Woods

    Abstract The Tasmanian devil (Sarcophilus harrisii) is the only mammalian species known to be affected by multiple transmissible cancers. Devil facial tumours 1 and 2 (DFT1 and DFT2) are independent neoplastic cell lineages that produce large, disfiguring cancers known as devil facial tumour disease (DFTD). The long-term persistence of wild Tasmanian devils is threatened due to the ability of DFTD cells to propagate as contagious allografts and the high mortality rate of DFTD. Recent studies have demonstrated that both DFT1 and DFT2 cancers originated from founder cells of the Schwann cell lineage, an uncommon origin of malignant cancer in humans. This unprecedented finding has revealed a potential predisposition of Tasmanian devils to transmissible cancers of the Schwann cell lineage. In this review, we compare the molecular nature of human Schwann cells and nerve sheath tumours with DFT1 and DFT2 to gain insights into the emergence of transmissible cancers in the Tasmanian devil. We discuss a potential mechanism, whereby Schwann cell plasticity and frequent wounding in Tasmanian devils combine with an inherent cancer predisposition and low genetic diversity to give rise to transmissible Schwann cell cancers in devils on rare occasions.

  • GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-03
    Raise Ahmad, Olivier Lahuna, Anissa Sidibe, Avais Daulat, Qiang Zhang, Marine Luka, Jean-Luc Guillaume, Sarah Gallet, François Guillonneau, Juliette Hamroune, Sophie Polo, Vincent Prévot, Philippe Delagrange, Julie Dam, Ralf Jockers

    Abstract Transmission of extracellular signals by G protein-coupled receptors typically relies on a cascade of intracellular events initiated by the activation of heterotrimeric G proteins or β-arrestins followed by effector activation/inhibition. Here, we report an alternative signal transduction mode used by the orphan GPR50 that relies on the nuclear translocation of its carboxyl-terminal domain (CTD). Activation of the calcium-dependent calpain protease cleaves off the CTD from the transmembrane-bound GPR50 core domain between Phe-408 and Ser-409 as determined by MALDI-TOF-mass spectrometry. The cytosolic CTD then translocates into the nucleus assisted by its ‘DPD’ motif, where it interacts with the general transcription factor TFII-I to regulate c-fos gene transcription. RNA-Seq analysis indicates a broad role of the CTD in modulating gene transcription with ~ 8000 differentially expressed genes. Our study describes a non-canonical, direct signaling mode of GPCRs to the nucleus with similarities to other receptor families such as the NOTCH receptor

  • Frizzled 1 and Wnt1 as new potential therapeutic targets in the traumatically injured spinal cord
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-03
    Pau González, Carlos González-Fernández, Yolanda Campos-Martín, Manuela Mollejo, Melissa Carballosa-Gautam, Alexander Marcillo, Michael Norenberg, Francisco Javier Rodríguez

    Abstract Despite the experimental evidence pointing to a significant role of the Wnt family of proteins in physiological and pathological rodent spinal cord functioning, its potential relevance in the healthy and traumatically injured human spinal cord as well as its therapeutic potential in spinal cord injury (SCI) are still poorly understood. To get further insight into these interesting issues, we first demonstrated by quantitative Real-Time PCR and simple immunohistochemistry that detectable mRNA expression of most Wnt components, as well as protein expression of all known Wnt receptors, can be found in the healthy human spinal cord, supporting its potential involvement in human spinal cord physiology. Moreover, evaluation of Frizzled (Fz) 1 expression by double immunohistochemistry showed that its spatio-temporal and cellular expression pattern in the traumatically injured human spinal cord is equivalent to that observed in a clinically relevant model of rat SCI and suggests its potential involvement in SCI progression/outcome. Accordingly, we found that long-term lentiviral-mediated overexpression of the Fz1 ligand Wnt1 after rat SCI improves motor functional recovery, increases myelin preservation and neuronal survival, and reduces early astroglial reactivity and NG2+ cell accumulation, highlighting the therapeutic potential of Wnt1 in this neuropathological situation.

  • Epigenetics in age-related macular degeneration: new discoveries and future perspectives
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-02
    M. Gemenetzi, A. J. Lotery

    Abstract The study of epigenetics has explained some of the ‘missing heritability’ of age-related macular degeneration (AMD). The epigenome also provides a substantial contribution to the organisation of the functional retina. There is emerging evidence of specific epigenetic mechanisms associated with AMD. This ‘AMD epigenome’ may offer the chance to develop novel AMD treatments.

  • Senescence in the pathogenesis of age-related macular degeneration
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-02
    Janusz Blasiak

    Age-related macular degeneration (AMD) is a complex eye disease underlined by the death of photoreceptors and degeneration of retinal pigment epithelium (RPE) and choriocapillaris (CC). The mechanism(s) responsible for massive and progressive retinal degeneration is not completely known. Senescence, a state of permanent inhibition of cell growth, may be induced by many factors important for AMD pathogenesis and results in senescence-associated secretory phenotype (SASP) that releases growth factors, cytokines, chemokines, proteases and other molecules inducing inflammation and other AMD-related effects. These effects can be induced in the affected cell and neighboring cells, leading to progression of AMD phenotype. Senescent cells also release reactive oxygen species that increase SASP propagation. Many other pathways of senescence-related AMD pathogenesis, including autophagy, the cGAS–STING signaling, degeneration of CC by membrane attack complex, can be considered. A2E, a fluorophore present in lipofuscin, amyloid-beta peptide and humanin, a mitochondria-derived peptide, may link AMD with senescence. Further studies on senescence in AMD pathogenesis to check the possibility of opening a perspective of the use of drugs killing senescent cells (senolytics) and terminating SASP bystander effects (senostatics) might be beneficial for AMD that at present is an incurable disease.

  • Introduction to the multi-author review on macular degeneration
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-02
    Anu Kauppinen

    Abstract Prolonged life expectancies contribute to the increasing prevalence of age-related macular degeneration (AMD) that is already the leading cause of severe vision loss among the elderly in developed countries. In dry AMD, the disease culminates into vast retinal atrophy, whereas the wet form is characterized by retinal edema and sudden vision loss due to neovascularization originating from the choroid beneath the Bruch’s membrane. There is no treatment for dry AMD and despite intravitreal injections of anti-vascular endothelial growth factor (VEGF) that suppress the neovessel formation, also wet AMD needs new therapies to prevent the disease progression and to serve patients lacking of positive response to current medicines. Knowledge on disease mechanisms is a prerequisite for the drug development, which is hindered by the multifactorial nature of AMD. Numerous distinguished publications have revealed AMD mechanisms at the cellular and molecular level and in this multi-author review, we take a bit broader look at the topic with some novel aspects.

  • The role of lymphocytes and phagocytes in age-related macular degeneration (AMD)
    Cell. Mol. Life Sci. (IF 7.014) Pub Date : 2020-01-02
    Verena Behnke, Anne Wolf, Thomas Langmann

    Abstract Age-related macular degeneration (AMD) is a leading cause of visual impairment of the elderly population. Since AMD is a multifactorial age-related disease with various genetic risk factors, the understanding of its complex pathophysiology is still limited. However, animal experiments, genome-wide association data and the molecular profiling of AMD patient samples have highlighted a key role of systemic and local immune processes that contribute to this chronic eye disease. In this overview article, we concentrate on the role of lymphocytes and mononuclear phagocytes and their interplay in triggering a persistent immune response in the AMD retina. We preferentially review findings from human immune cell analyses and complement these with related findings in experimental models. We conclude that both immune cell types as their signaling network may be a rich source to identify novel molecular targets for immunomodulation in AMD.

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