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  • Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2020-01-03
    Liu Y, Zhang C, Wang S, et al.

    After leaving the testis, mammalian sperm undergoes a sequential maturation process in the epididymis followed by capacitation during its movement through the female reproductive tract. These phenotypic changes are associated with modification of protein phosphorylation and membrane remodeling, which is requisite for sperm to acquire forward motility and induce fertilization. However, the molecular mechanisms underlying sperm maturation and capacitation are still not fully understood. Herein, we show that PPP3R2, a testis-specific regulatory subunit of protein phosphatase 3 (an isoform of calcineurin in testis), is essential for sperm maturation and capacitation. Knockout of Ppp3r2 in mice leads to male sterility due to sperm motility impairment and morphological defects. One very noteworthy change includes increases in sperm membrane stiffness. Moreover, PPP3R2 regulates sperm maturation and capacitation via: (1) modulation of membrane diffusion barrier function at the annulus; (2) facilitation of cholesterol efflux during sperm capacitation. Taken together, PPP3R2 plays a critical role in modulating cholesterol efflux and mediating dynamic control of membrane remodeling during sperm maturation and capacitation.

    更新日期:2020-01-27
  • Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2020-01-03
    Na Y, Jung D, Song J, et al.

    Interleukin-10 (IL-10) is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases. Cellular metabolism is a critical determinant of immune cell function; however, it is currently unclear whether metabolic processes are specifically involved in IL-10 production. In this study, we aimed to find the central metabolic molecule regulating IL-10 production of macrophages, which are the main producers of IL-10. Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model. Among them, pyruvate dehydrogenase kinase (PDK)-dependent acute glycolysis was negatively involved in IL-10 production. Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression. Mechanistically, PDK inhibition increased IL-10 production via profound phosphorylation of AMP-activated protein kinase alpha 1 (AMPKα1) by restricting glucose uptake in lipopolysaccharide-stimulated macrophages. AMPKα1 consequently activated p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase and cAMP responsive element binding protein (CREB) to regulate IL-10 production. Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.

    更新日期:2020-01-27
  • Identification of small molecules for accelerating the differentiation of GABA interneurons from human pluripotent stem cells
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2020-01-26
    Shen L, Yuan F, Hong Y, et al.

    Graphical abstractGraphic abstract.

    更新日期:2020-01-27
  • Glucocorticoid receptor–IRS-1 axis controls EMT and the metastasis of breast cancers
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-02-06
    Shi W, Wang D, Yuan X, et al.

    Glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes that are important for various biological functions, including tumor growth and metastatic progression. However, the cellular and biological effects of GR remain poorly understood. Here, we investigated the role of GR and its underlying mechanism in mediating breast cancer cell survival and metastasis. We observed that the GR levels were increased in drug-resistant breast cancer cells and in metastatic breast cancer samples. GR promoted tumor cell invasion and lung metastasis in vivo. The GR expression levels were negatively correlated with the survival rates of breast cancer patients. Both ectopic expression and knockdown of GR revealed that GR is a strong inducer of epithelial-to-mesenchymal transition (EMT), which is consistent with its effects on cell survival and metastasis. GR suppressed the expression of insulin receptor substrate 1 (IRS-1) by acting as an IRS-1 transcriptional repressor. In addition, GR has an opposite effect on the expression levels of IRS-2, indicating that GR is able to differentially regulate the IRS-1 and IRS-2 expression. The cellular and biological effects elicited by GR were consistent with the reduced levels of IRS-1 observed in cancer cells, and GR-mediated IRS-1 suppression activated the ERK2 MAP kinase pathway, which is required for GR-mediated EMT. Taken together, our results indicate that GR–IRS-1 signaling axis plays an essential role in regulating the survival, invasion, and metastasis of breast cancer cells.

    更新日期:2020-01-22
  • Mitochondrial ROS promote macrophage pyroptosis by inducing GSDMD oxidation
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-03-12
    Wang Y, Shi P, Chen Q, et al.

    Disrupted mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation are often associated with macrophage pyroptosis. It remains unclear how these forms of mitochondrial dysfunction relate to inflammasome activation and gasdermin-D (Gsdmd) cleavage, two central steps of the pyroptotic process. Here, we also found MMP collapse and ROS generation induced by Nlrp3 inflammasome activation as previous studies reported. The elimination of ROS alleviated the cleavage of Gsdmd, suggesting that Gsdmd cleavage occurs downstream of ROS release. Consistent with this result, hydrogen peroxide treatment augmented the cleavage of Gsdmd by caspase-1. Indeed, four amino acid residues of Gsdmd were oxidized under oxidative stress in macrophages. The efficiency of Gsdmd cleavage by inflammatory caspase-1 was dramatically reduced when oxidative modification was blocked by mutation of these amino acid residues. These results demonstrate that Gsdmd oxidation serves as a de novo mechanism by which mitochondrial ROS promote Nlrp3 inflammasome-dependent pyroptotic cell death.

    更新日期:2020-01-22
  • Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-03-18
    Kong H, Jiang C, Hu L, et al.

    The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and sequestosome-1 (SQSTM1/p62). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.

    更新日期:2020-01-22
  • A harlequin ichthyosis pig model with a novel ABCA12 mutation can be rescued by acitretin treatment
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-03-29
    Wang X, Cao C, Li Y, et al.

    Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but improvements are still needed. However, the ABCA12 null mice failed to respond to retinoid treatment, which impedes the development of novel cure strategies for HI. Here we generated an ethylnitrosourea mutagenic HI pig model (named Z9), which carries a novel deep intronic mutation IVS49-727 A>G in the ABCA12 gene, resulting in abnormal mRNA splicing and truncated protein production. Z9 pigs exhibit significant clinical symptom as human patients with HI. Most importantly, systemic retinoid treatment significantly prolonged the life span of the mutant pigs via improving epidermal maturation, decreasing epidermal apoptosis, and triggering the expression of ABCA6. Taken together, this pig model perfectly resembles the clinical symptom and molecular pathology of patients with HI and will be useful for understanding mechanistic insight and developing therapeutic strategies.

    更新日期:2020-01-22
  • 更新日期:2020-01-22
  • CILP-2 is a novel secreted protein and associated with insulin resistance
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-06-06
    Wu T, Zhang Q, Wu S, et al.

    Genetic association studies have implicated that cartilage intermediate layer protein 2 (CILP-2) confers the risk susceptibility for type 2 diabetes (T2DM). However, it is still unknown whether CILP-2 is involved in the regulation of glucose homeostasis and insulin resistance (IR). In the current study, we initially observed that CILP-2 as a secreted protein was detected in both conditioned medium and lysates of cells transfected with an overexpressed vector. We then found that circulating CILP-2 levels had a progressive increase from normal to impaired glucose tolerance (a pre-diabetic status) and then to diabetes, which was correlated positively with waist-to-hip ratio, triglyceride, fasting blood glucose, 2-h blood glucose after glucose overload, HbA1c, fasting insulin, 2-h plasma insulin after glucose overload, and homeostasis model assessment of insulin resistance but negatively with HDL-C. CILP-2 expression was increased in the liver and muscle but decreased in adipose tissues of obese mice or T2DM patients. Furthermore, we demonstrated that CILP-2 circulating levels were affected by OGTT and Exenatide. CILP-2 overexpression resulted in impaired glucose tolerance and hepatic IR in vivo and increased PEPCK expression whereas suppressed phosphorylation of insulin receptor and Akt kinase in vitro. Based on these findings, we have identified a direct interaction between CILP-2 and PEPCK and suggested that CILP-2 plays an important role in the regulation of hepatic glucose production.

    更新日期:2020-01-22
  • Corrigendum to ‘The long and the short of it: the MDM4 tail so far’
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-12-26
    Haupt S, Mejía-Hernández J, Vijayakumaran R, et al.

    In this article (p.240, MDM4 Inhibition section, second paragraph), the drug name of Aileron stapled peptide ‘ALN-6924’ was incorrectly cited (as ‘ALN-6942’). This mistake was due to human error. The conclusions of the review are not affected and the authors apologize for this error.

    更新日期:2020-01-22
  • Corrigendum to ‘Understanding p53 functions through p53 antibodies’
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-12-26
    Sabapathy K, Lane D.

    In this article, we have inadvertently omitted the support from the funding agency, which should be as follows:

    更新日期:2020-01-22
  • 更新日期:2020-01-22
  • Corrigendum to ‘p53 balances between tissue hierarchy and anarchy’
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-12-26
    Koifman G, Aloni-Grinstein R, Rotter V.

    In this article (p.559, third paragraph), the reference in ‘The identified ESC gene signature-derived genes correlated with poor patient survival and human tumors harboring p53 hotspot mutations (Lonetto et al., 2018)’ was incorrectly cited. It should be changed to ‘(Koifman et al., 2018)’. The conclusions of the review are not affected and the authors apologize for this error.

    更新日期:2020-01-22
  • An HBV-encoded miRNA activates innate immunity to restrict HBV replication
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-12-21
    Zhao X, Sun L, Mu T, et al.

    We previously identified that the hepatitis B virus (HBV) encodes a microRNA (HBV-miR-3) that restrains HBV replication by targeting the HBV transcript. However, whether HBV-miR-3 affects host innate immunity to modulate HBV replication remains unclear. Here, we examined the vital functions of HBV-miR-3 in the innate immune response after HBV infection. We found that HBV-miR-3 expression gradually increased in a dose- and time-dependent manner in HBV-infected HepG2-NTCP cells. HBV-miR-3 activated the JAK/STAT signaling pathway by downregulating SOCS5 in hepatocytes, thereby enhancing the IFN-induced anti-HBV effect. In addition, HBV-miR-3 in exosomes facilitated the M1 polarization of macrophages. Furthermore, exosomes containing HBV-miR-3 enhanced the secretion of IL-6 via inhibiting the SOCS5-mediated ubiquitination of EGFR. In short, these results demonstrate that HBV-miR-3 activates the innate immune response to restrain HBV replication by multiple pathways, which may suppress HBV-induced acute liver cell injury and affect the progression of persistent HBV infection.

    更新日期:2020-01-04
  • BET inhibition prevents aberrant RUNX1 and ERG transcription in STAG2 mutant leukaemia cells
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2020-01-03
    Antony J, Gimenez G, Taylor T, et al.

    cohesinSTAG2RUNX1ERGmegakaryocyteCRISPR-Cas9chromatininducibleenhancer

    更新日期:2020-01-04
  • Methylation of PLK1 by SET7/9 ensures accurate kinetochore–microtubule dynamics
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-12-21
    Yu R, Wu H, Ismail H, et al.

    Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying PLK1 activation have been extensively studied, the regulatory mechanisms that couple PLK1 activity to accurate chromosome segregation are not well understood. In particular, PLK1 is implicated in stabilizing kinetochore–microtubule attachments, but how kinetochore PLK1 activity is regulated to avoid hyperstabilized kinetochore–microtubules in mitosis remains elusive. Here, we show that kinetochore PLK1 kinase activity is modulated by SET7/9 via lysine methylation during early mitosis. The SET7/9-elicited dimethylation occurs at the Lys191 of PLK1, which tunes down its activity by limiting ATP utilization. Overexpression of the non-methylatable PLK1 mutant or chemical inhibition of SET7/9 methyltransferase activity resulted in mitotic arrest due to destabilized kinetochore–microtubule attachments. These data suggest that kinetochore PLK1 is essential for stable kinetochore–microtubule attachments and methylation by SET7/9 promotes dynamic kinetochore–microtubule attachments for accurate error correction. Our findings define a novel homeostatic regulation at the kinetochore that integrates protein phosphorylation and methylation with accurate chromosome segregation for maintenance of genomic stability.

    更新日期:2019-12-21
  • Integration of peripheral circadian clock and energy metabolism in metabolic tissues
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-12-21
    Zhang Y, Zhang W, Liu C.

    The mammalian circadian clock precisely controls various physiological processes, including energy metabolism, to help body adapt to the diurnal light/dark cycles induced by the earth autorotation. Although the clock and metabolism are tightly coupled and interacted, the molecular mechanism through which these two pathways are integrated remains largely unknown. In the past 10 years, we have been focusing on this important scientific question and innovatively proposed three integration modes, including the “parallel connection” mode orchestrated by nuclear factors, the “serial connection” mode orchestrated by clock-controlled proteins, and the “combinational connection” mode regulated by metabolites. Here we summarize and discuss the molecular mechanisms of the integration between peripheral circadian clock and energy metabolism in metabolic tissues.

    更新日期:2019-12-21
  • Aberrant alternative splicing in breast cancer
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-05-08
    Yang Q, Zhao J, Zhang W, et al.

    Alternative splicing is critical for human gene expression regulation, which plays a determined role in expanding the diversity of functional proteins. Importantly, alternative splicing is a hallmark of cancer and a potential target for cancer therapeutics. Based on the statistical data, breast cancer is one of the top leading causes of cancer-related deaths in women worldwide. Strikingly, alternative splicing is closely associated with breast cancer development. Here, we seek to provide a general review of the relationship between alternative splicing and breast cancer. We introduce the process of alternative splicing and its regulatory role in cancers. In addition, we highlight the functions of aberrant alternative splicing and mutations of splicing factors in breast cancer progression. Moreover, we discuss the role of alternative splicing in cancer drug resistance and the potential of being targets for cancer therapeutics.

    更新日期:2019-11-30
  • Auto-regulatory feedback by RNA-binding proteins
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-05-08
    Müller-McNicoll M, Rossbach O, Hui J, et al.

    RNA-binding proteins (RBPs) are key regulators in post-transcriptional control of gene expression. Mutations that alter their activity or abundance have been implicated in numerous diseases such as neurodegenerative disorders and various types of cancer. This highlights the importance of RBP proteostasis and the necessity to tightly control the expression levels and activities of RBPs. In many cases, RBPs engage in an auto-regulatory feedback by directly binding to and influencing the fate of their own mRNAs, exerting control over their own expression. For this feedback control, RBPs employ a variety of mechanisms operating at all levels of post-transcriptional regulation of gene expression. Here we review RBP-mediated autogenous feedback regulation that either serves to maintain protein abundance within a physiological range (by negative feedback) or generates binary, genetic on/off switches important for e.g. cell fate decisions (by positive feedback).

    更新日期:2019-11-30
  • Long noncoding RNA in cardiac aging and disease
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-06-01
    Lozano-Vidal N, Bink D, Boon R, et al.

    Cardiovascular diseases (CVDs) are the main cause of morbidity and mortality in Western society and present an important age-related risk. With the constant rise in life expectancy, prevalence of CVD in the population will likely increase further. New therapies, especially in the elderly, are needed to combat CVD. This review is focused on the role of long noncoding RNA (lncRNA) in CVD. RNA sequencing experiments in the past decade showed that most RNA does not code for protein, but many RNAs function as ncRNA. Here, we summarize the recent findings of lncRNA regulation in the diseased heart. The potential use of these RNAs as biomarkers of cardiac disease prediction is also discussed.

    更新日期:2019-11-30
  • Functional impacts of non-coding RNA processing on enhancer activity and target gene expression
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-06-06
    Ntini E, Marsico A, Bindereif A.

    Tight regulation of gene expression is orchestrated by enhancers. Through recent research advancements, it is becoming clear that enhancers are not solely distal regulatory elements harboring transcription factor binding sites and decorated with specific histone marks, but they rather display signatures of active transcription, showing distinct degrees of transcription unit organization. Thereby, a substantial fraction of enhancers give rise to different species of non-coding RNA transcripts with an unprecedented range of potential functions. In this review, we bring together data from recent studies indicating that non-coding RNA transcription from active enhancers, as well as enhancer-produced long non-coding RNA transcripts, may modulate or define the functional regulatory potential of the cognate enhancer. In addition, we summarize supporting evidence that RNA processing of the enhancer-associated long non-coding RNA transcripts may constitute an additional layer of regulation of enhancer activity, which contributes to the control and final outcome of enhancer-targeted gene expression.

    更新日期:2019-11-30
  • POLIII-derived non-coding RNAs acting as scaffolds and decoys
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-06-01
    Täuber H, Hüttelmaier S, Köhn M, et al.

    A large variety of eukaryotic small structured POLIII-derived non-coding RNAs (ncRNAs) have been described in the past. However, for only few, e.g. 7SL and H1/MRP families, cellular functions are well understood. For the vast majority of these transcripts, cellular functions remain unknown. Recent findings on the role of Y RNAs and other POLIII-derived ncRNAs suggest an evolutionarily conserved function of these ncRNAs in the assembly and function of ribonucleoprotein complexes (RNPs). These RNPs provide cellular `machineries’, which are essential for guiding the fate and function of a variety of RNAs. In this review, we summarize current knowledge on the role of POLIII-derived ncRNAs in the assembly and function of RNPs. We propose that these ncRNAs serve as scaffolding factors that `chaperone’ RNA-binding proteins (RBPs) to form functional RNPs. In addition or associated with this role, some small ncRNAs act as molecular decoys impairing the RBP-guided control of RNA fate by competing with other RNA substrates. This suggests that POLIII-derived ncRNAs serve essential and conserved roles in the assembly of larger RNPs and thus the control of gene expression by indirectly guiding the fate of mRNAs and lncRNAs.

    更新日期:2019-11-30
  • Marking RNA: m6A writers, readers, and functions in Arabidopsis
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-07-23
    Reichel M, Köster T, Staiger D.

    N6-methyladenosine (m6A) emerges as an important modification in eukaryotic mRNAs. m6A has first been reported in 1974, and its functional significance in mammalian gene regulation and importance for proper development have been well established. An arsenal of writer, eraser, and reader proteins accomplish deposition, removal, and interpretation of the m6A mark, resulting in dynamic function. This led to the concept of an epitranscriptome, the compendium of RNA species with chemical modification of the nucleobases in the cell, in analogy to the epigenome. While m6A has long been known to also exist in plant mRNAs, proteins involved in m6A metabolism have only recently been detected by mutant analysis, homology search, and mRNA interactome capture in the reference plant Arabidopsis thaliana. Dysregulation of the m6A modification causes severe developmental abnormalities of leaves and roots and altered timing of reproductive development. Furthermore, m6A modification affects viral infection. Here, we discuss recent progress in identifying m6A sites transcriptome-wide, in identifying the molecular players involved in writing, removing, and reading the mark, and in assigning functions to this RNA modification in A. thaliana. We highlight similarities and differences to m6A modification in mammals and provide an outlook on important questions that remain to be addressed.

    更新日期:2019-11-30
  • Challenges and perspectives for structural biology of lncRNAs—the example of the Xist lncRNA A-repeats
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-07-23
    Jones A, Sattler M, Bindereif A.

    Following the discovery of numerous long non-coding RNA (lncRNA) transcripts in the human genome, their important roles in biology and human disease are emerging. Recent progress in experimental methods has enabled the identification of structural features of lncRNAs. However, determining high-resolution structures is challenging as lncRNAs are expected to be dynamic and adopt multiple conformations, which may be modulated by interaction with protein binding partners. The X-inactive specific transcript (Xist) is necessary for X inactivation during dosage compensation in female placental mammals and one of the best-studied lncRNAs. Recent progress has provided new insights into the domain organization, molecular features, and RNA binding proteins that interact with distinct regions of Xist. The A-repeats located at the 5′ end of the transcript are of particular interest as they are essential for mediating silencing of the inactive X chromosome. Here, we discuss recent progress with elucidating structural features of the Xist lncRNA, focusing on the A-repeats. We discuss the experimental and computational approaches employed that have led to distinct structural models, likely reflecting the intrinsic dynamics of this RNA. The presence of multiple dynamic conformations may also play an important role in the formation of the associated RNPs, thus influencing the molecular mechanism underlying the biological function of the Xist A-repeats. We propose that integrative approaches that combine biochemical experiments and high-resolution structural biology in vitro with chemical probing and functional studies in vivo are required to unravel the molecular mechanisms of lncRNAs.

    更新日期:2019-11-30
  • IRES-mediated cap-independent translation, a path leading to hidden proteome
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-09-03
    Yang Y, Wang Z, Bindereif A.

    Most eukaryotic mRNAs are translated in a cap-dependent fashion; however, under stress conditions, the cap-independent translation driven by internal ribosomal entry sites (IRESs) can serve as an alternative mechanism for protein production. Many IRESs have been discovered from viral or cellular mRNAs to promote ribosome assembly and initiate translation by recruiting different trans-acting factors. Although the mechanisms of translation initiation driven by viral IRESs are relatively well understood, the existence of cellular IRESs is still under debate due to the limitations of translation reporter systems used to assay IRES activities. A recent screen identified > 1000 putative IRESs from viral and human mRNAs, expanding the scope and mechanism for cap-independent translation. Additionally, a large number of circular RNAs lacking free ends were identified in eukaryotic cells, many of which are found to be translated through IRESs. These findings suggest that IRESs may play a previously unappreciated role in driving translation of the new type of mRNA, implying a hidden proteome produced from cap-independent translation.

    更新日期:2019-11-30
  • IDH1 fine-tunes cap-dependent translation initiation
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-08-13
    Liu L, Lu J, Li F, et al.

    The metabolic enzyme isocitrate dehydrogenase 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Its mutation often leads to aberrant gene expression in cancer. IDH1 was reported to bind thousands of RNA transcripts in a sequence-dependent manner; yet, the functional significance of this RNA-binding activity remains elusive. Here, we report that IDH1 promotes mRNA translation via direct associations with polysome mRNA and translation machinery. Comprehensive proteomic analysis in embryonic stem cells (ESCs) revealed striking enrichment of ribosomal proteins and translation regulators in IDH1-bound protein interactomes. We performed ribosomal profiling and analyzed mRNA transcripts that are associated with actively translating polysomes. Interestingly, knockout of IDH1 in ESCs led to significant downregulation of polysome-bound mRNA in IDH1 targets and subtle upregulation of ribosome densities at the start codon, indicating inefficient translation initiation upon loss of IDH1. Tethering IDH1 to a luciferase mRNA via the MS2-MBP system promotes luciferase translation, independently of the catalytic activity of IDH1. Intriguingly, IDH1 fails to enhance luciferase translation driven by an internal ribosome entry site. Together, these results reveal an unforeseen role of IDH1 in fine-tuning cap-dependent translation via the initiation step.

    更新日期:2019-11-30
  • Non-coding RNAs in cancers with chromosomal rearrangements: the signatures, causes, functions and implications
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-07-26
    Han C, Sun L, Wang W, et al.

    Chromosomal translocation leads to the juxtaposition of two otherwise separate DNA loci, which could result in gene fusion. These rearrangements at the DNA level are catastrophic events and often have causal roles in tumorigenesis. The oncogenic DNA messages are transferred to RNA molecules, which are in most cases translated into cancerous fusion proteins. Gene expression programs and signaling pathways are altered in these cytogenetically abnormal contexts. Notably, non-coding RNAs have attracted increasing attention and are believed to be tightly associated with chromosome-rearranged cancers. These RNAs not only function as modulators in downstream pathways but also directly affect chromosomal translocation or the associated products. This review summarizes recent research advances on the relationship between non-coding RNAs and chromosomal translocations and on diverse functions of non-coding RNAs in cancers with chromosomal rearrangements.

    更新日期:2019-11-30
  • Intricacies in the cross talk between metabolic enzymes, RNA, and protein translation
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-09-03
    Lv Y, Tariq M, Guo X, et al.

    The development of techniques allowing the systematic capture of the RNA-bound proteome has yielded many surprises. Among these, metabolic enzymes have been frequently detected as RNA-binding proteins (RBPs) by different profiling methodologies in various cell types (Hentze et al., 2018). Compared to previous—more simplistic—views, it is now known that cellular metabolism (not only limited to the tricarboxylic acid, TCA, cycle) is compartmentalized. In fact, metabolic enzymes translocate to the nucleus and are enriched at actively transcribed loci, where they sustain epigenetic/epitranscriptomic marks through localized metabolite production (Mews et al., 2017). It has been proposed that the interaction with nascent RNAs facilitates the anchorage of metabolic enzymes at target loci (Bao et al., 2018), and it is plausible that mature RNAs work in the same way to assist metabolic reactions in the cytoplasm. Yet, it is becoming increasingly evident that the interaction of metabolic enzymes with RNA also has metabolism-independent functions, and protein translation is emerging as a key missing nexus (Figure 1A). For example, the glycolytic enzyme pyruvate kinase muscle 2 (PKM2) promotes protein translation through simultaneous binding to target mRNAs and ribosomal components (Simsek et al., 2017). Thus, deeper understanding of the relationship between RNA and metabolic enzymes is necessary for gaining a complete model of metabolism and other cellular functions as a whole.

    更新日期:2019-11-30
  • A joint adventure of Sino-German researchers to explore the wild world of RNAs
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-10-22
    Bindereif A, Wang Z.

    NA biology has developed in recent years to a new emerging field, with new surprises and insights ranging from basic mechanisms to topics of clinical interest and opening up biotechnological applications in molecular medicine and novel therapeutic options. Here, we edit this Special Issue of Journal of Molecular Cell Biology on RNA biology, combining a series of reviews and research articles that reflect most of the current trends and topics emerging from recent Chinese–German interactions in RNA research.

    更新日期:2019-11-30
  • A combined computational pipeline to detect circular RNAs in human cancer cells under hypoxic stress
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-09-27
    Di Liddo A, de Oliveira Freitas Machado C, Fischer S, et al.

    Hypoxia is associated with several diseases, including cancer. Cells that are deprived of adequate oxygen supply trigger transcriptional and post-transcriptional responses, which control cellular pathways such as angiogenesis, proliferation, and metabolic adaptation. Circular RNAs (circRNAs) are a novel class of mainly non-coding RNAs, which have been implicated in multiple cancers and attract increasing attention as potential biomarkers. Here, we characterize the circRNA signatures of three different cancer cell lines from cervical (HeLa), breast (MCF-7), and lung (A549) cancer under hypoxia. In order to reliably detect circRNAs, we integrate available tools with custom approaches for quantification and statistical analysis. Using this consolidated computational pipeline, we identify ~12000 circRNAs in the three cancer cell lines. Their molecular characteristics point to an involvement of complementary RNA sequences as well as trans-acting factors in circRNA biogenesis, such as the RNA-binding protein HNRNPC. Notably, we detect a number of circRNAs that are more abundant than their linear counterparts. In addition, 64 circRNAs significantly change in abundance upon hypoxia, in most cases in a cell type-specific manner. In summary, we present a comparative circRNA profiling in human cancer cell lines, which promises novel insights into the biogenesis and function of circRNAs under hypoxic stress.

    更新日期:2019-11-30
  • Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-11-19
    Hong L, Yan L, Xin Z, et al.

    Chemotherapeutic agents are extensively used to treat malignancies. However, chemotherapy-induced ovarian damage and reduced fertility are severe side effects. Recently, stem cell transplantation has been reported to be an effective strategy for premature ovarian insufficiency (POI) treatment, but safety can still be an issue in stem cell-based therapy. Here, we show the protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) on a cisplatin-induced ovarian injury model. hUCMSC-CM can relieve cisplatin-induced depletion of follicles and preserve fertility. In addition, hUCMSC-CM can decrease apoptosis of oocytes and granulosa cells induced by cisplatin. RNA sequencing analysis reveals the differentially expressed genes of ovaries after cisplatin and hUCMSC-CM treatments, including genes involved in cell apoptosis. Furthermore, we show that the granulocyte colony-stimulating factor (G-CSF)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway plays an important role in protecting granulosa cells from cisplatin-induced apoptosis. Together, we confirm the protective effects of hUCMSC-CM on ovarian reserve and fertility in mice treated with cisplatin, highlighting the remarkable therapeutic effects of hUCMSC-CM.

    更新日期:2019-11-19
  • Maternal miR-202-5p is required for zebrafish primordial germ cell migration by protecting small GTPase Cdc42
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-11-19
    Jin Y, Liu W, Xiang Y, et al.

    In many lower animals, germ cell formation, migration and maintenance depend on maternally provided determinants in germ plasm. In zebrafish, these processes have been extensively studied in terms of RNA binding proteins and other coding genes. The role of small non-coding RNAs in the regulation of primordial germ cell (PGC) development remains largely unknown and poorly investigated, even though growing interests for the importance of miRNAs involved in a wide variety of biological processes. Here, we reported the role and mechanism of the germ plasm-specific miRNA miR-202-5p in PGC migration; (i) both maternal loss and knockdown of miR-202-5p impaired PGC migration indicated by the mislocalization and reduced number of PGCs, (ii) cdc42se1 was a direct target gene of miR-202-5p, and overexpression of Cdc42se1 in PGCs caused PGC migration defects similar to those observed in loss of miR-202-5p mutants; (iii) Cdc42se1 not only interacted with Cdc42, but also inhibited cdc42 transcription, and overexpression of Cdc42 could rescue PGC migration defects in Cdc42se1 overexpressed embryos. Thus, miR-202-5p regulates PGC migration by directly targeting and repressing Cdc42se1 to protect the expression of Cdc42, which interacts with Actin to direct PGC migration.

    更新日期:2019-11-19
  • Basonuclin 1 deficiency causes testicular premature aging: BNC1 cooperates with TAF7L to regulate spermatogenesis
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-11-04
    Li J, Liu Y, Xu H, et al.

    Basonuclin (BNC1) is expressed primarily in proliferative keratinocytes and gametogenic cells. However, its roles in spermatogenesis and testicular aging were not clear. Previously we discovered a heterozygous BNC1 truncation mutation in a premature ovarian insufficiency pedigree. In this study, we found that male mice carrying the truncation mutation exhibited progressively fertility loss and testicular premature aging. Genome-wide expression profiling and direct binding studies (by chromatin immunoprecipitation sequencing) with BNC1 in mouse testis identified several spermatogenesis-specific gene promoters targeted by BNC1 including kelch-like family member 10 (Klhl10), testis expressed 14 (Tex14), and spermatogenesis and centriole associated 1 (Spatc1). Moreover, biochemical analysis showed that BNC1 was associated with TATA-box binding protein-associated factor 7 like (TAF7L), a germ cell-specific paralogue of the transcription factor IID subunit TAF7, both in vitro and in testis, suggesting that BNC1 might directly cooperate with TAF7L to regulate spermatogenesis. The truncation mutation disabled nuclear translocation of the BNC1/TAF7L complex, thus, disturbing expression of related genes and leading to testicular premature aging. Similarly, expressions of BNC1, TAF7L, Y-box-binding protein 2 (YBX2), outer dense fiber of sperm tails 1 (ODF1), and glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) were significantly decreased in the testis of men with non-obstructive azoospermia. The present study adds to the understanding of the physiology of male reproductive aging and the mechanism of spermatogenic failure in infertile men.

    更新日期:2019-11-04
  • p38α MAP kinase promotes asthmatic inflammation through modulation of alternatively activated macrophages.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-06-30
    Li-Nian Huang,Lei Sun,Li-Ming Liu,Hui-Hui Zhang,Zhong-Bo Liang,Yan Rui,Jun-Feng Hu,Yong Zhang,John W Christman,Feng Qian

    更新日期:2019-11-01
  • The C-terminal low-complexity domain involved in liquid-liquid phase separation is required for BRD4 function in vivo.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-05-09
    Chenlu Wang,Erhao Zhang,Fan Wu,Yufeng Sun,Yingcheng Wu,Baorui Tao,Yue Ming,Yuanpei Xu,Renfang Mao,Yihui Fan

    更新日期:2019-11-01
  • HDAC-dependent decrease in histone crotonylation during DNA damage.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-03-14
    Enas R Abu-Zhayia,Feras E Machour,Nabieh Ayoub

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • New insights into neurobiology.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2018-11-14
    Jiarui Wu

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Ten years for JMCB.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2018-12-28
    Jiarui Wu

    更新日期:2019-11-01
  • A parallel mechanism underlying frizzle in domestic chickens.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2018-06-06
    Xing Guo,Yan-Qing Li,Ming-Shan Wang,Zhi-Bin Wang,Quan Zhang,Yong Shao,Run-Shen Jiang,Sheng Wang,Chen-Dong Ma,Robert W Murphy,Guang-Qin Wang,Jing Dong,Li Zhang,Dong-Dong Wu,Bing-Wang Du,Min-Sheng Peng,Ya-Ping Zhang

    更新日期:2019-11-01
  • Restoring p53 in cancer: the promises and the challenges.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-07-10
    Guillermina Lozano

    更新日期:2019-11-01
  • Gain-of-function mutant p53: history and speculation.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-07-10
    Jill Bargonetti,Carol Prives

    更新日期:2019-11-01
  • p53: updates on mechanisms, biology and therapy (I).
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-06-22
    David P Lane,Chandra S Verma

    更新日期:2019-11-01
  • p53: updates on mechanisms, biology and therapy (II).
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-06-22
    David P Lane,Chandra S Verma

    更新日期:2019-11-01
  • The many faces of p53: something for everyone.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-03-30
    Arnold J Levine

    更新日期:2019-11-01
  • Modulation of Fatty Acid Synthase by ATR checkpoint kinase Rad3.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : null
    Shuwan Qiu,Sheng Liu,Zannati Ferdous Zaoti,Xuejuan Wang,Gang Cai

    更新日期:2019-11-01
  • New players critical for breast cancer.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2018-09-29
    Hua Lu

    更新日期:2019-11-01
  • Transgenic Strategies to Generate Heterogeneous Hepatic Cancer Models in Zebrafish.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-08-02
    Fei Fei,Lei Wang,Shaoyang Sun,Kunpeng Lv,Yuxiao Yao,Jingjing Wang,Min Yu,Xu Wang

    更新日期:2019-11-01
  • Systematical study of the mechanistic factors regulating genome dynamics in vivo by CRISPRsie.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-07-23
    Deqiang Han,Yu Hong,Xueying Mai,Qingtao Hu,Guangqing Lu,Jinzhi Duan,Jingru Xu,Xiaofang Si,Yu Zhang

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Nuclear actin switch of the INO80 remodeler.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2018-12-19
    Jun Wu,Yimin Lao,Bing Li

    更新日期:2019-11-01
  • Sqh is involved in the regulation of Ci stability in Hh signaling pathway.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2015-11-01
    Chunying Liu,Yue Xiong,Jing Feng,Lei Zhang,Yun Zhao

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Resident Prrx1 lineage stromal cells promote T cell survival in the spleen.
    J. Mol. Cell Biol. (IF 4.671) Pub Date : 2019-01-10
    Wanyao Zhang,Qian Yu,Huijuan Liu,Baojie Li

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • 更新日期:2019-11-01
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