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  • NAD(P) transhydrogenase has vital non‐mitochondrial functions in malaria parasite transmission
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-17
    Sadia Saeed; Annie Z Tremp; Vikram Sharma; Edwin Lasonder; Johannes T Dessens

    Nicotinamide adenine dinucleotide (NAD) and its phosphorylated form (NADP) are vital for cell function in all organisms and form cofactors to a host of enzymes in catabolic and anabolic processes. NAD(P) transhydrogenases (NTHs) catalyse hydride ion transfer between NAD(H) and NADP(H). Membrane‐bound NTH isoforms reside in the cytoplasmic membrane of bacteria, and the inner membrane of mitochondria in metazoans, where they generate NADPH. Here, we show that malaria parasites encode a single membrane‐bound NTH that localises to the crystalloid, an organelle required for sporozoite transmission from mosquitos to vertebrates. We demonstrate that NTH has an essential structural role in crystalloid biogenesis, whilst its enzymatic activity is required for sporozoite development. This pinpoints an essential function in sporogony to the activity of a single crystalloid protein. Its additional presence in the apicoplast of sporozoites identifies NTH as a likely supplier of NADPH for this organelle during liver infection. Our findings reveal that Plasmodium species have co‐opted NTH to a variety of non‐mitochondrial organelles to provide a critical source of NADPH reducing power.

    更新日期:2020-01-17
  • Tau acetylates and stabilizes β‐catenin thereby promoting cell survival
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-13
    Enjie Liu; Qiuzhi Zhou; Ao‐Ji Xie; Xiaoguang Li; Mengzhu Li; Jinwang Ye; Shihong Li; Dan Ke; Qun Wang; Zhi‐Peng Xu; Li Li; Ying Yang; Gong‐Ping Liu; Xiao‐Chuan Wang; Hong‐Lian Li; Jian‐Zhi Wang

    Overexpressing Tau counteracts apoptosis and increases dephosphorylated β‐catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate β‐catenin at K49 in a concentration‐, time‐, and pH‐dependent manner. β‐catenin K49 acetylation inhibits its phosphorylation and its ubiquitination‐associated proteolysis, thus increasing β‐catenin protein levels. K49 acetylation further promotes nuclear translocation and the transcriptional activity of β‐catenin, and increases the expression of survival‐promoting genes (bcl2 and survivin), counteracting apoptosis. Mutation of Tau's acetyltransferase domain or co‐expressing non‐acetylatable β‐catenin‐K49R prevents increased β‐catenin signaling and abolishes the anti‐apoptotic function of Tau. Our data reveal that Tau preserves β‐catenin by acetylating K49, and upregulated β‐catenin/survival signaling in turn mediates the anti‐apoptotic effect of Tau.

    更新日期:2020-01-13
  • RNF152 positively regulates TLR/IL‐1R signaling by enhancing MyD88 oligomerization
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-13
    Mei‐Guang Xiong; Zhi‐Sheng Xu; Yu‐Hui Li; Su‐Yun Wang; Yan‐Yi Wang; Yong Ran

    Toll‐like receptors (TLRs) are important pattern recognition receptors (PRRs) that are critical for the defense against invading pathogens. IL‐1β is an important pro‐inflammatory cytokine that also plays pivotal roles in shaping the adaptive immune response. TLRs and interleukin‐1 receptor (IL‐1R) share similar cytosolic domains and signaling processes. In this study, we identify the E3 ubiquitin ligase RNF152 as a positive regulator of TLR/IL‐1R‐mediated signaling. Overexpression of RNF152 potentiates IL‐1β‐ and LPS‐induced NF‐κB activation in an ubiquitination‐independent manner, whereas knockdown of RNF152 has the opposite effects. RNF152‐deficient mice produce less inflammatory cytokines in response to LPS and are more resistant to LPS‐induced lethal endotoxemia. Mechanistically, RNF152 interacts with the adaptor protein MyD88 and enhances oligomerization of MyD88, which is essential for the recruitment of downstream signaling components and activation of TLR/IL‐1R‐mediated signal transduction. Our findings suggest that RNF152‐mediated oligomerization of MyD88 is important for TLR/IL‐1R‐mediated inflammatory response.

    更新日期:2020-01-13
  • CRMP2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-09
    Jakub Ziak; Romana Weissova; Kateřina Jeřábková; Martina Janikova; Roy Maimon; Tomas Petrasek; Barbora Pukajova; Marie Kleisnerova; Mengzhe Wang; Monika S Brill; Petr Kasparek; Xunlei Zhou; Gonzalo Alvarez‐Bolado; Radislav Sedlacek; Thomas Misgeld; Ales Stuchlik; Eran Perlson; Martin Balastik

    Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2−/− mice we demonstrate that CRMP2 has a moderate effect on Sema3A‐dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2−/− mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2−/− mice display ASD‐related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F‐dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.

    更新日期:2020-01-10
  • Another hijack! Some enteroviruses co‐opt the c10orf76/PI4KB complex for their own good
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-09
    Laetitia Voilquin; Thomas Di Mattia; Fabien Alpy

    Enteroviruses, members of the Picornaviridae family, are non‐enveloped and single‐stranded RNA viruses responsible for several human diseases. During infection, these viruses build membrane‐bound organelles, called replication organelles (ROs), where new virions are assembled. ROs are highly enriched in phosphatidylinositol 4‐phosphate (PI4P) produced by the host lipid kinase PI4KB. In this issue of EMBO Reports, McPhail et al [1] characterize a complex, formed by PI4KB and the c10orf76 protein, which is involved in PI4P production. They show that this machinery is hijacked by specific enteroviruses such as coxsackievirus A10 for their replication.

    更新日期:2020-01-10
  • Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-09
    Jinhua Li; Yu Bo Yang Sun; Weiyi Chen; Jinjin Fan; Songhui Li; Xinli Qu; Qikang Chen; Riling Chen; Dajian Zhu; Jinfeng Zhang; Zhuguo Wu; Honggang Chi; Simon Crawford; Viola Oorschot; Victor G Puelles; Peter G Kerr; Yi Ren; Susan K Nilsson; Mark Christian; Huanwen Tang; Wei Chen; John F Bertram; David J Nikolic‐Paterson; Xueqing Yu

    Diabetic nephropathy (DN) is the leading cause of end‐stage kidney disease. TGF‐β1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti‐Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.

    更新日期:2020-01-09
  • NBR1‐mediated p62‐liquid droplets enhance the Keap1‐Nrf2 system
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-09
    Pablo Sánchez‐Martín; Yu‐shin Sou; Shun Kageyama; Masato Koike; Satoshi Waguri; Masaaki Komatsu

    p62/SQSTM1 is a multivalent protein that has the ability to cause liquid–liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non‐canonical activation of the Keap1‐Nrf2 system, a major oxidative stress response pathway. Here, we show a role of neighbor of BRCA1 gene 1 (NBR1), an autophagy receptor structurally similar to p62/SQSTM1, in p62‐liquid droplet formation and Keap1‐Nrf2 pathway activation. Overexpression of NBR1 blocks selective degradation of p62/SQSTM1 through autophagy and promotes the accumulation and phosphorylation of p62/SQSTM1 in liquid‐like bodies, which is required for the activation of Nrf2. NBR1 is induced in response to oxidative stress, which triggers p62‐mediated Nrf2 activation. Conversely, loss of Nbr1 suppresses not only the formation of p62/SQSTM1‐liquid droplets, but also of p62‐dependent Nrf2 activation during oxidative stress. Taken together, our results show that NBR1 mediates p62/SQSTM1‐liquid droplet formation to activate the Keap1‐Nrf2 pathway.

    更新日期:2020-01-09
  • One repressor to rule them all: ANCO1 links YAP and AIB1
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-02
    Can Zhang; Kenneth Moberg

    The transcriptional co‐activators YAP and AIB1 individually promote breast cancer progression, but are not known to be mechanistically linked. A study published in this issue of EMBO Reports [1] now shows that YAP‐AIB1 form a physical complex in breast epithelial cells that cooperates in both activation and, unexpectedly, repression of key breast cancer genes. The repressive effect is due to the recruitment of ANCO1, a previously defined AIB1 interactor [2] that binds and inhibits the YAP‐AIB1 complex. These data identify ANCO1 as a candidate tumor suppressor through YAP‐AIB1 inhibition and could hint at a broader crosstalk between pathways that utilize YAP and AIB1 to control epithelial homeostasis.

    更新日期:2020-01-07
  • An extracellular microRNA can rescue lives in sepsis
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-14
    Kelly Van Looveren; Lise Van Wyngene; Claude Libert

    Sepsis, or blood poisoning, is a savage response of the body to infection. It can lead to organ failure, blood pressure decline, heart failure, and coma. Between 20 and 30 million people suffer from sepsis each year, leading to 8 million deaths. Although certain people are more at risk than others (young children, elderly), anyone can develop sepsis. Patients are resuscitated and treated with antibiotics, and their organ functions are supported. Despite the investment in sepsis research during the previous decades, successful clinical trials are scarce and sepsis remains one of the most difficult and deadly unmet medical needs of today. A study in this issue now provides new insight into sepsis and points to a therapeutic future [1].

    更新日期:2020-01-07
  • Loss of ANCO1 repression at AIB1/YAP targets drives breast cancer progression
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-02
    Max H Kushner; Virginie Ory; Garrett T Graham; Ghada M Sharif; William B Kietzman; Sophia Thevissen; Meng Yuan; Marcel O Schmidt; Anton Wellstein; Anna T Riegel
    更新日期:2020-01-07
  • A distinct metabolic state arises during the emergence of 2‐cell‐like cells
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-18
    Diego Rodriguez‐Terrones; Götz Hartleben; Xavier Gaume; André Eid; Manuel Guthmann; Ane Iturbide; Maria‐Elena Torres‐Padilla

    Pluripotent stem cells are thought of as a surrogate of early developmental stages that sustain the capacity to generate all cell types in the body, thereby constituting an invaluable tool to address the mechanisms underlying cellular plasticity. In the mouse, cells resembling totipotent 2‐cell‐stage embryos (2‐cell‐like cells) arise at a very low frequency in embryonic stem cell (ESC) cultures. However, the extent to which these early‐embryonic‐like cells recapitulate the molecular features of the early embryo is unclear. Here, we have undertaken a characterization of some of the metabolic features of early‐embryonic‐like cells in culture. Our data indicate that early‐embryonic‐like cells exhibit decreased glycolytic and respiratory activity, lower levels of reactive oxygen species and increased glucose uptake, suggesting a shift of the metabolic programme during 2‐cell‐like cell reprogramming. Accordingly, we find that 2‐cell‐like cells can be induced by defined metabolites. Thus, in addition to their transcriptional and chromatin features, 2‐cell‐like cells recapitulate some of the metabolic features of their in vivo counterpart. Altogether, our work underscores a distinct metabolic state of early‐embryonic‐like cells and identifies compounds that can induce their emergence in vitro.

    更新日期:2020-01-07
  • PHF6 promotes non‐homologous end joining and G2 checkpoint recovery
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-29
    Daniël O Warmerdam; Ignacio Alonso‐de Vega; Wouter W Wiegant; Bram van den Broek; Magdalena B Rother; Rob MF Wolthuis; Raimundo Freire; Haico van Attikum; René H Medema; Veronique AJ Smits
    更新日期:2020-01-07
  • PP2A‐B56 binds to Apc1 and promotes Cdc20 association with the APC/C ubiquitin ligase in mitosis
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-11
    Kazuyuki Fujimitsu; Hiroyuki Yamano

    Cell cycle progression and genome stability are regulated by a ubiquitin ligase, the anaphase‐promoting complex/cyclosome (APC/C). Cyclin‐dependent kinase 1 (Cdk1) has long been implicated in APC/C activation; however, the molecular mechanisms of governing this process in vivo are largely unknown. Recently, a Cdk1‐dependent phosphorylation relay within Apc3‐Apc1 subunits has been shown to alleviate Apc1‐mediated auto‐inhibition by which a mitotic APC/C co‐activator Cdc20 binds to and activates the APC/C. However, the underlying mechanism for dephosphorylation of Cdc20 and APC/C remains elusive. Here, we show that a disordered loop domain of Apc1 (Apc1‐loop500) directly binds the B56 regulatory subunit of protein phosphatase 2A (PP2A) and stimulates Cdc20 loading to the APC/C. Using the APC/C reconstitution system in Xenopus egg extracts, we demonstrate that mutations in Apc1‐loop500 that abolish B56 binding decrease Cdc20 loading and APC/C‐dependent ubiquitylation. Conversely, a non‐phosphorylatable mutant Cdc20 can efficiently bind the APC/C even when PP2A‐B56 binding is impeded. Furthermore, PP2A‐B56 preferentially dephosphorylates Cdc20 over the Apc1 inhibitory domain. These results indicate that Apc1‐loop500 plays a role in dephosphorylating Cdc20, promoting APC/C‐Cdc20 complex formation in mitosis.

    更新日期:2020-01-07
  • MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-13
    Cong Wang; Ricarda Richter‐Dennerlein; David Pacheu‐Grau; Fan Liu; Ying Zhu; Sven Dennerlein; Peter Rehling
    更新日期:2020-01-07
  • pH‐controlled histone acetylation amplifies melanocyte differentiation downstream of MITF
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-11
    Desingu Ayyappa Raja; Vishvabandhu Gotherwal; Shaunak A Burse; Yogaspoorthi J Subramaniam; Farina Sultan; Archana Vats; Hemlata Gautam; Babita Sharma; Sachin Sharma; Archana Singh; Sridhar Sivasubbu; Rajesh S Gokhale; Vivek T Natarajan
    更新日期:2020-01-07
  • Extracellular microRNA 130b‐3p inhibits eCIRP‐induced inflammation
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-14
    Steven D Gurien; Monowar Aziz; Hui Jin; Haichao Wang; Mingzhu He; Yousef Al‐Abed; Jeffrey M Nicastro; Gene F Coppa; Ping Wang
    更新日期:2020-01-07
  • TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-04
    Zhaolong Li; Chen Huan; Hong Wang; Yue Liu; Xin Liu; Xing Su; Jinghua Yu; Zhilei Zhao; Xiao‐Fang Yu; Baisong Zheng; Wenyan Zhang

    SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21‐mediated degradation of SAMHD1 also affects SAMHD1‐dependent restriction of HIV‐1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.

    更新日期:2020-01-07
  • Schistosomal extracellular vesicle‐enclosed miRNAs modulate host T helper cell differentiation
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-11
    Tal Meningher; Yiftah Barsheshet; Yifat Ofir‐Birin; Daniel Gold; Boris Brant; Elya Dekel; Yechezkel Sidi; Eli Schwartz; Neta Regev‐Rudzki; Orly Avni; Dror Avni

    During the chronic stage of Schistosoma infection, the female lays fertile eggs, triggering a strong anti‐parasitic type 2 helper T‐cell (Th2) immune response. It is unclear how this Th2 response gradually declines even though the worms live for years and continue to produce eggs. Here, we show that Schistosoma mansoni downregulates Th2 differentiation in an antigen‐presenting cell‐independent manner, by modulating the Th2‐specific transcriptional program. Adult schistosomes secrete miRNA‐harboring extracellular vesicles that are internalized by Th cells in vitro. Schistosomal miRNAs are found also in T helper cells isolated from Peyer's patches and mesenteric lymph nodes of infected mice. In T helper cells, the schistosomal miR‐10 targets MAP3K7 and consequently downmodulates NF‐κB activity, a critical transcription factor for Th2 differentiation and function. Our results explain, at least partially, how schistosomes tune down the Th2 response, and provide further insight into the reciprocal geographic distribution between high prevalence of parasitic infections and immune disorders such as allergy. Furthermore, this worm‐host crosstalk mechanism can be harnessed to develop diagnostic and therapeutic approaches for human schistosomiasis and Th2‐associated diseases.

    更新日期:2020-01-07
  • QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-23
    Huanyu Lu; Zichen Ye; Yue Zhai; Li Wang; Ying Liu; Jiye Wang; Wenbin Zhang; Wenjing Luo; Zifan Lu; Jingyuan Chen

    Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA‐binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI‐deficient mice are resistant to high‐fat‐diet (HFD)‐induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue‐specific depletion of QKI in mice enhances cold‐induced thermogenesis, thereby preventing hypothermia in response to cold stimulus. Further mechanistic analysis reveals that QKI is transcriptionally induced by the cAMP‐cAMP response element‐binding protein (CREB) axis and restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1α. These findings extend our knowledge of the significance of posttranscriptional regulation in adipose metabolic homeostasis and provide a potential therapeutic target to defend against obesity and its related metabolic diseases.

    更新日期:2020-01-07
  • Effector loading onto the VgrG carrier activates type VI secretion system assembly
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-05
    Chih‐Feng Wu; Yun‐Wei Lien; Devanand Bondage; Jer‐Sheng Lin; Martin Pilhofer; Yu‐Ling Shih; Jeff H Chang; Erh‐Min Lai

    The type VI secretion system (T6SS) is used by many bacteria to engage in social behavior and can affect the health of its host plant or animal. Because activities associated with T6SSs are often costly, T6SSs must be tightly regulated. However, our knowledge regarding how T6SS assembly and contraction are regulated remains limited. Using the plant pathogen Agrobacterium tumefaciens, we show that effectors are not just passengers but also impact on T6SS assembly. The A. tumefaciens strain C58 encodes one T6SS and two Tde DNase toxin effectors used as major weapons for interbacterial competition. Here, we demonstrate that loading of Tde effectors onto their cognate carriers, the VgrG spikes, is required for active T6SS secretion. The assembly of the TssBC contractile sheath occurs only in the presence of Tde effectors. The requirement of effector loading for efficient T6SS secretion was also validated in other A. tumefaciens strains. We propose that such a mechanism is used by bacteria as a strategy for efficacious T6SS firing and to ensure that effectors are loaded onto the T6SS prior to completing its assembly.

    更新日期:2020-01-07
  • Arpin is critical for phagocytosis in macrophages and is targeted by human rhinovirus
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-13
    Jamil Jubrail; Kshanti Africano‐Gomez; Floriane Herit; Anna Mularski; Pierre Bourdoncle; Lisa Oberg; Elisabeth Israelsson; Pierre‐Regis Burgel; Gaell Mayer; Danen M Cunoosamy; Nisha Kurian; Florence Niedergang
    更新日期:2020-01-07
  • Aβ43‐producing PS1 FAD mutants cause altered substrate interactions and respond to γ‐secretase modulation
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-25
    Johannes Trambauer; Rosa María Rodríguez Sarmiento; Akio Fukumori; Regina Feederle; Karlheinz Baumann; Harald Steiner

    Abnormal generation of neurotoxic amyloid‐β peptide (Aβ) 42/43 species due to mutations in the catalytic presenilin 1 (PS1) subunit of γ‐secretase is the major cause of familial Alzheimer's disease (FAD). Deeper mechanistic insight on the generation of Aβ43 is still lacking, and it is unclear whether γ‐secretase modulators (GSMs) can reduce the levels of this Aβ species. By comparing several types of Aβ43‐generating FAD mutants, we observe that very high levels of Aβ43 are often produced when presenilin function is severely impaired. Altered interactions of C99, the precursor of Aβ, are found for all mutants and are independent of their particular effect on Aβ production. Furthermore, unlike previously described GSMs, the novel compound RO7019009 can effectively lower Aβ43 production of all mutants. Finally, substrate‐binding competition experiments suggest that RO7019009 acts mechanistically after initial C99 binding. We conclude that altered C99 interactions are a common feature of diverse types of PS1 FAD mutants and that also patients with Aβ43‐generating FAD mutations could in principle be treated by GSMs.

    更新日期:2020-01-07
  • TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-11
    Lina Herhaus; Ramachandra M Bhaskara; Alf Håkon Lystad; Uxía Gestal‐Mato; Adriana Covarrubias‐Pinto; Florian Bonn; Anne Simonsen; Gerhard Hummer; Ivan Dikic
    更新日期:2020-01-07
  • Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-21
    Yusha Wang; Yewei Huang; Jiaqi Liu; Jinna Zhang; Mingming Xu; Zhiyuan You; Chao Peng; Zhefeng Gong; Wei Liu
    更新日期:2020-01-07
  • Wnt regulates amino acid transporter Slc7a5 and so constrains the integrated stress response in mouse embryos
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-02
    Nadège Poncet; Pamela A Halley; Christopher Lipina; Marek Gierliński; Alwyn Dady; Gail A Singer; Melanie Febrer; Yun‐Bo Shi; Terry P Yamaguchi; Peter M Taylor; Kate G Storey
    更新日期:2020-01-07
  • Non‐apoptotic TRAIL function modulates NK cell activity during viral infection
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-19
    Ludmila Cardoso Alves; Michael D Berger; Thodoris Koutsandreas; Nick Kirschke; Christoph Lauer; Roman Spörri; Aristotelis Chatziioannou; Nadia Corazza; Philippe Krebs
    更新日期:2020-01-07
  • PCAF‐mediated acetylation of ISX recruits BRD4 to promote epithelial‐mesenchymal transition
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-07
    Li‐Ting Wang; Kwei‐Yan Liu; Wen‐Yih Jeng; Cheng‐Ming Chiang; Chee‐Yin Chai; Shyh‐Shin Chiou; Ming‐Shyang Huang; Kazunari K Yokoyama; Shen‐Nien Wang; Shau‐Ku Huang; Shih‐Hsien Hsu

    Epigenetic regulation is important for cancer progression; however, the underlying mechanisms, particularly those involving protein acetylation, remain to be fully understood. Here, we show that p300/CBP‐associated factor (PCAF)‐dependent acetylation of the transcription factor intestine‐specific homeobox (ISX) regulates epithelial–mesenchymal transition (EMT) and promotes cancer metastasis. Mechanistically, PCAF acetylation of ISX at lysine 69 promotes the interaction with acetylated bromodomain‐containing protein 4 (BRD4) at lysine 332 in tumor cells, and the translocation of the resulting complex into the nucleus. There, it binds to promoters of EMT genes, where acetylation of histone 3 at lysines 9, 14, and 18 initiates chromatin remodeling and subsequent transcriptional activation. Ectopic ISX expression enhances EMT marker expression, including TWIST1, Snail1, and VEGF, induces cancer metastasis, but suppresses E‐cadherin expression. In lung cancer, ectopic expression of PCAF–ISX–BRD4 axis components correlates with clinical metastatic features and poor prognosis. These results suggest that the PCAF–ISX–BRD4 axis mediates EMT signaling and regulates tumor initiation and metastasis.

    更新日期:2020-01-07
  • PCAF, ISX, and BRD4: a maleficent alliance serving lung cancer malignancy
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-07
    Marc P Stemmler

    Tumor progression and malignancy are frequently associated with aberrant activation of epithelial–mesenchymal transition (EMT), which orchestrates dramatic changes in gene expression, involving genetic and epigenetic regulation. External stimuli generated by tumor–stroma interactions need to be adequately processed to specifically alter expression of key EMT transcription factors and associated genes. In this issue of EMBO Reports, Wang and colleagues demonstrate how epigenetic modifiers are utilized to induce EMT and metastasis [1]. Acetylation of intestine‐specific homeobox (ISX) by p300/CBP‐associated factor (PCAF) induces a cascade that results in Snail and Twist activation through histone modifications by a novel complex of PCAF, ISX, and bromodomain‐containing protein 4 (BRD4). These findings open novel possibilities of therapeutic intervention to inhibit EMT and metastasis in lung cancer.

    更新日期:2020-01-07
  • Peroxisomal fission is modulated by the mitochondrial Rho‐GTPases, Miro1 and Miro2
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-02
    Christian Covill‐Cooke; Viktoriya S Toncheva; James Drew; Nicol Birsa; Guillermo López‐Doménech; Josef T Kittler

    Peroxisomes are essential for a number of cellular functions, including reactive oxygen species metabolism, fatty acid β‐oxidation and lipid synthesis. To ensure optimal functionality, peroxisomal size, shape and number must be dynamically maintained; however, many aspects of how this is regulated remain poorly characterised. Here, we show that the localisation of Miro1 and Miro2—outer mitochondrial membrane proteins essential for mitochondrial trafficking—to peroxisomes is not required for basal peroxisomal distribution and long‐range trafficking, but rather for the maintenance of peroxisomal size and morphology through peroxisomal fission. Mechanistically, this is achieved by Miro negatively regulating Drp1‐dependent fission, a function that is shared with the mitochondria. We further find that the peroxisomal localisation of Miro is regulated by its first GTPase domain and is mediated by an interaction through its transmembrane domain with the peroxisomal‐membrane protein chaperone, Pex19. Our work highlights a shared regulatory role of Miro in maintaining the morphology of both peroxisomes and mitochondria, supporting a crosstalk between peroxisomal and mitochondrial biology.

    更新日期:2020-01-02
  • Succinate induces skeletal muscle fiber remodeling via SUNCR1 signaling
    EMBO Rep. (IF 8.383) Pub Date : 2019-07-18
    Tao Wang; Ya‐Qiong Xu; Ye‐Xian Yuan; Ping‐Wen Xu; Cha Zhang; Fan Li; Li‐Na Wang; Cong Yin; Lin Zhang; Xing‐Cai Cai; Can‐Jun Zhu; Jing‐Ren Xu; Bing‐Qing Liang; Sarah Schaul; Pei‐Pei Xie; Dong Yue; Zheng‐Rui Liao; Lu‐Lu Yu; Lv Luo; Gan Zhou; Jin‐Ping Yang; Zhi‐Hui He; Man Du; Yu‐Ping Zhou; Bai‐Chuan Deng; Song‐Bo Wang; Ping Gao; Xiao‐Tong Zhu; Qian‐Yun Xi; Yong‐Liang Zhang; Gang Shu; Qing‐Yan Jiang
    更新日期:2020-01-02
  • Heme oxygenase‐1 deficiency triggers exhaustion of hematopoietic stem cells
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-29
    Krzysztof Szade; Monika Zukowska; Agata Szade; Witold Nowak; Izabella Skulimowska; Maciej Ciesla; Karolina Bukowska‐Strakova; Gunsagar Singh Gulati; Neli Kachamakova‐Trojanowska; Anna Kusienicka; Elisa Einwallner; Jacek Kijowski; Szymon Czauderna; Harald Esterbauer; Vladimir Benes; Irving L Weissman; Jozef Dulak; Alicja Jozkowicz

    While intrinsic changes in aging hematopoietic stem cells (HSCs) are well characterized, it remains unclear how extrinsic factors affect HSC aging. Here, we demonstrate that cells in the niche—endothelial cells (ECs) and CXCL12‐abundant reticular cells (CARs)—highly express the heme‐degrading enzyme, heme oxygenase 1 (HO‐1), but then decrease its expression with age. HO‐1‐deficient animals (HO‐1−/−) have altered numbers of ECs and CARs that produce less hematopoietic factors. HSCs co‐cultured in vitro with HO‐1−/− mesenchymal stromal cells expand, but have altered kinetic of growth and differentiation of derived colonies. HSCs from young HO‐1−/− animals have reduced quiescence and regenerative potential. Young HO‐1−/− HSCs exhibit features of premature exhaustion on the transcriptional and functional level. HO‐1+/+ HSCs transplanted into HO‐1−/− recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO‐1−/− HSCs to the HO‐1+/+ recipients recovers the regenerative potential of HO‐1−/− HSCs and reverses their transcriptional alterations. Thus, HSC‐extrinsic activity of HO‐1 prevents HSCs from premature exhaustion and may restore the function of aged HSCs.

    更新日期:2019-12-30
  • Monomeric cohesin state revealed by live‐cell single‐molecule spectroscopy
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-29
    Wenjie Liu; Elisheva Biton; Anjali Pathania; Avi Matityahu; Joseph Irudayaraj; Itay Onn

    The cohesin complex plays an important role in the maintenance of genome stability. Cohesin is composed of four core subunits and a set of regulatory subunits that interact with the core subunits. Less is known about cohesin dynamics in live cells and on the contribution of individual subunits to the overall complex. Understanding the tethering mechanism of cohesin is still a challenge, especially because the proposed mechanisms are still not conclusive. Models proposed to describe tethering depend on either the monomeric cohesin ring or a cohesin dimer. Here, we investigate the role of cohesin dynamics and stoichiometry in live yeast cells at single‐molecule resolution. We explore the effect of regulatory subunit deletion on cohesin mobility and found that depletion of different regulatory subunits has opposing effects. Finally, we show that cohesin exists mostly as a canonical monomer throughout the cell cycle, and its monomeric form is independent of its regulatory factors. Our results demonstrate that single‐molecule tools have the potential to provide new insights into the cohesin mechanism of action in live cells.

    更新日期:2019-12-30
  • CEP41‐mediated ciliary tubulin glutamylation drives angiogenesis through AURKA‐dependent deciliation
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-29
    Soo Mi Ki; Ji Hyun Kim; So Yeon Won; Shin Ji Oh; In Young Lee; Young‐Ki Bae; Ki Wha Chung; Byung‐Ok Choi; Boyoun Park; Eui‐Ju Choi; Ji Eun Lee

    The endothelial cilium is a microtubule‐based organelle responsible for blood flow‐induced mechanosensation and signal transduction during angiogenesis. The precise function and mechanisms by which ciliary mechanosensation occurs, however, are poorly understood. Although posttranslational modifications (PTMs) of cytoplasmic tubulin are known to be important in angiogenesis, the specific roles of ciliary tubulin PTMs play remain unclear. Here, we report that loss of centrosomal protein 41 (CEP41) results in vascular impairment in human cell lines and zebrafish, implying a previously unknown pro‐angiogenic role for CEP41. We show that proper control of tubulin glutamylation by CEP41 is necessary for cilia disassembly and that is involved in endothelial cell (EC) dynamics such as migration and tubulogenesis. We show that in ECs responding to shear stress or hypoxia, CEP41 activates Aurora kinase A (AURKA) and upregulates expression of VEGFA and VEGFR2 through ciliary tubulin glutamylation, as well as leads to the deciliation. We further show that in hypoxia‐induced angiogenesis, CEP41 is responsible for the activation of HIF1α to trigger the AURKA‐VEGF pathway. Overall, our results suggest the CEP41‐HIF1α‐AURKA‐VEGF axis as a key molecular mechanism of angiogenesis and demonstrate how important ciliary tubulin glutamylation is in mechanosense‐responded EC dynamics.

    更新日期:2019-12-30
  • DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-29
    Yerui Lai; Anjiang Zhao; Minghong Tan; Mengliu Yang; Yao Lin; Shengbing Li; Jinlin Song; Hongting Zheng; Zhiming Zhu; Dongfang Liu; Chaohong Liu; Ling Li; Gangyi Yang

    The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high‐fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5‐deficient hepatocytes. Importantly, in liver‐specific Raptor knockout mice and associated hepatocytes, the effects of an adeno‐associated virus (AAV8)‐ or adenovirus‐mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5–Raptor interaction is indispensable for the DOCK5‐mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

    更新日期:2019-12-30
  • HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53‐dependent mitochondrial apoptosis
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-23
    Marilena Castelli; Danilo Piobbico; Martina Chiacchiaretta; Cinzia Brunacci; Stefania Pieroni; Daniela Bartoli; Marco Gargaro; Francesca Fallarino; Paolo Puccetti; Silvia Soddu; Maria Agnese Della‐Fazia; Giuseppe Servillo

    Apoptotic signalling by p53 occurs at both transcriptional and non‐transcriptional levels, as p53 may act as a direct apoptogenic stimulus via activation of the intrinsic mitochondrial pathway. HOPS is a highly conserved, ubiquitously expressed shuttling protein with an ubiquitin‐like domain. We generated Hops−/− mice and observed that they are viable with no apparent phenotypic defects. However, when treated with chemotherapeutic agents, Hops−/− mice display a significant reduction in apoptosis, suggesting an impaired ability to respond to genotoxic stressors. We show that HOPS acts as a regulator of cytoplasmic p53 levels and function. By binding p53, HOPS inhibits p53 proteasomal degradation and favours p53 recruitment to mitochondria and apoptosis induction. By interfering with importin α, HOPS further increases p53 cytoplasmic levels. Thus, HOPS promotes the p53‐dependent mitochondrial apoptosis pathway by preserving cytoplasmic p53 from both degradation and nuclear uptake.

    更新日期:2019-12-23
  • SMC5/6 acts jointly with Fanconi anemia factors to support DNA repair and genome stability
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-23
    Francesco Rossi; Anne Helbling‐Leclerc; Ryotaro Kawasumi; Nanda Kumar Jegadesan; Xinlin Xu; Pierre Devulder; Takuya Abe; Minoru Takata; Dongyi Xu; Filippo Rosselli; Dana Branzei

    SMC5/6 function in genome integrity remains elusive. Here, we show that SMC5 dysfunction in avian DT40 B cells causes mitotic delay and hypersensitivity toward DNA intra‐ and inter‐strand crosslinkers (ICLs), with smc5 mutants being epistatic to FANCC and FANCM mutations affecting the Fanconi anemia (FA) pathway. Mutations in the checkpoint clamp loader RAD17 and the DNA helicase DDX11, acting in an FA‐like pathway, do not aggravate the damage sensitivity caused by SMC5 dysfunction in DT40 cells. SMC5/6 knockdown in HeLa cells causes MMC sensitivity, increases nuclear bridges, micronuclei, and mitotic catastrophes in a manner similar and non‐additive to FANCD2 knockdown. In both DT40 and HeLa systems, SMC5/6 deficiency does not affect FANCD2 ubiquitylation and, unlike FANCD2 depletion, RAD51 focus formation. SMC5/6 components further physically interact with FANCD2‐I in human cells. Altogether, our data suggest that SMC5/6 functions jointly with the FA pathway to support genome integrity and DNA repair and may be implicated in FA or FA‐related human disorders.

    更新日期:2019-12-23
  • CrRLK1L receptor‐like kinases HERK1 and ANJEA are female determinants of pollen tube reception
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-23
    Sergio Galindo‐Trigo; Noel Blanco‐Touriñán; Thomas A DeFalco; Eloise S Wells; Julie E Gray; Cyril Zipfel; Lisa M Smith

    Communication between the gametophytes is vital for angiosperm fertilisation. Multiple CrRLK1L‐type receptor kinases prevent premature pollen tube burst, while another CrRLK1L protein, FERONIA (FER), is required for pollen tube reception in the female gametophyte. We report here the identification of two additional CrRLK1L homologues, HERCULES RECEPTOR KINASE 1 (HERK1) and ANJEA (ANJ), which act redundantly to promote pollen tube growth arrest at the synergid cells. HERK1 and ANJ localise to the filiform apparatus of the synergid cells in unfertilised ovules, and in herk1 anj mutants, a majority of ovules remain unfertilised due to pollen tube overgrowth, together indicating that HERK1 and ANJ act as female determinants for fertilisation. As in fer mutants, the synergid cell‐specific, endomembrane protein NORTIA (NTA) is not relocalised after pollen tube reception; however, unlike fer mutants, reactive oxygen species levels are unaffected in herk1 anj double mutants. Both ANJ and HERK1 associate with FER and its proposed co‐receptor LORELEI (LRE) in planta. Together, our data indicate that HERK1 and ANJ act with FER to mediate female–male gametophyte interactions during plant fertilisation.

    更新日期:2019-12-23
  • Arginine methylation‐dependent LSD1 stability promotes invasion and metastasis of breast cancer
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-12
    Jiwei Liu; Jingxin Feng; Lili Li; Luyao Lin; Jiafei Ji; Cong Lin; Lingxia Liu; Na Zhang; Dandan Duan; Zhongwei Li; Baiqu Huang; Yu Zhang; Jun Lu

    Histone lysine demethylase 1 (LSD1), the first identified histone demethylase, is overexpressed in multiple tumor types, including breast cancer. However, the mechanisms that cause LSD1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 4 (PRMT4 or CARM1) dimethylates LSD1 at R838, which promotes the binding of the deubiquitinase USP7, resulting in the deubiquitination and stabilization of LSD1. Moreover, CARM1‐ and USP7‐dependent LSD1 stabilization plays a key role in repressing E‐cadherin and activating vimentin transcription through promoter H3K4me2 and H3K9me2 demethylation, respectively, which promotes invasion and metastasis of breast cancer cells. Consistently, LSD1 arginine methylation levels correlate with tumor grade in human malignant breast carcinoma samples. Our findings unveil a unique mechanism controlling LSD1 stability by arginine methylation, also highlighting the role of the CARM1‐USP7‐LSD1 axis in breast cancer progression.

    更新日期:2019-12-13
  • Armitage determines Piwi−piRISC processing from precursor formation and quality control to inter‐organelle translocation
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-12
    Haruna Yamashiro; Mayu Negishi; Tatsuki Kinoshita; Hirotsugu Ishizu; Hitoshi Ohtani; Mikiko C Siomi

    Piwi and piRNA form the piRNA‐induced silencing complex (piRISC) to repress transposons. In the current model, Armitage (Armi) brings the Piwi–piRISC precursor (pre‐piRISC) to mitochondria, where Zucchini‐dependent piRISC maturation occurs. Here, we show that Armi is necessary for Piwi–pre‐piRISC formation at Yb bodies and that Armi triggers the exit of Piwi–pre‐piRISC from Yb bodies and the translocation to mitochondria. Piwi–pre‐piRISC resist leaving Yb bodies until Armi binds Piwi–pre‐piRISC through the piRNA precursors. The lack of the Armi N‐terminus also blocks the Piwi–pre‐piRISC exit from Yb bodies. Thus, Armi determines Piwi–piRISC processing, in a multilayered manner, from precursor formation and quality control to inter‐organelle translocation for maturation.

    更新日期:2019-12-13
  • Anti‐HIV‐1 antibodies trigger non‐lytic complement deposition on infected cells
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-12
    Jérémy Dufloo; Florence Guivel‐Benhassine; Julian Buchrieser; Valérie Lorin; Ludivine Grzelak; Emilie Dupouy; Guillaume Mestrallet; Katia Bourdic; Olivier Lambotte; Hugo Mouquet; Timothée Bruel; Olivier Schwartz

    The effect of anti‐HIV‐1 antibodies on complement activation at the surface of infected cells remains partly understood. Here, we show that a subset of anti‐Envelope (Env) broadly neutralizing antibodies (bNAbs), targeting the CD4 binding site and the V3 loop, triggers C3 deposition and complement‐dependent cytotoxicity (CDC) on Raji cells engineered to express high surface levels of HIV‐1 Env. Primary CD4 T cells infected with laboratory‐adapted or primary HIV‐1 strains and treated with bNAbs are susceptible to C3 deposition but not to rapid CDC. The cellular protein CD59 and viral proteins Vpu and Nef protect infected cells from CDC mediated by bNAbs or by polyclonal IgGs from HIV‐positive individuals. However, complement deposition accelerates the disappearance of infected cells within a few days of culture. Altogether, our results uncover the contribution of complement to the antiviral activity of anti‐HIV‐1 bNAbs.

    更新日期:2019-12-13
  • Characterization of the c10orf76‐PI4KB complex and its necessity for Golgi PI4P levels and enterovirus replication
    EMBO Rep. (IF 8.383) Pub Date : 2019-12-12
    Jacob A McPhail; Heyrhyoung R Lyoo; Joshua G Pemberton; Reece M Hoffmann; Wendy van Elst; Jeroen RPM Strating; Meredith L Jenkins; Jordan TB Stariha; Cameron J Powell; Martin J Boulanger; Tamas Balla; Frank JM van Kuppeveld; John E Burke

    The lipid kinase PI4KB, which generates phosphatidylinositol 4‐phosphate (PI4P), is a key enzyme in regulating membrane transport and is also hijacked by multiple picornaviruses to mediate viral replication. PI4KB can interact with multiple protein binding partners, which are differentially manipulated by picornaviruses to facilitate replication. The protein c10orf76 is a PI4KB‐associated protein that increases PI4P levels at the Golgi and is essential for the viral replication of specific enteroviruses. We used hydrogen–deuterium exchange mass spectrometry to characterize the c10orf76‐PI4KB complex and reveal that binding is mediated by the kinase linker of PI4KB, with formation of the heterodimeric complex modulated by PKA‐dependent phosphorylation. Complex‐disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76‐PI4KB complex is required for the replication of c10orf76‐dependent enteroviruses. Intriguingly, c10orf76 also contributed to proper Arf1 activation at the Golgi, providing a putative mechanism for the c10orf76‐dependent increase in PI4P levels at the Golgi.

    更新日期:2019-12-13
  • A nuclear licence to silence transposons
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-16
    Poppy A Gould; Helen M Rowe

    Transposon silencing requires the histone methyltransferase SETDB1. In this issue of EMBO Reports, Tsusaka et al [1] and Osumi et al [2] illustrate how the cofactor ATF7IP and its fly homolog Windei (Wde) regulate the methyltransferase function of SETDB1 through its nuclear licensing. The new insight gained from these two articles will shift how we think about epigenetic regulation and its multiple layers of control.

    更新日期:2019-12-05
  • Causal roles of mitochondrial dynamics in longevity and healthy aging
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-31
    Arpit Sharma; Hannah J Smith; Pallas Yao; William B Mair

    Mitochondria are organized in the cell in the form of a dynamic, interconnected network. Mitochondrial dynamics, regulated by mitochondrial fission, fusion, and trafficking, ensure restructuring of this complex reticulum in response to nutrient availability, molecular signals, and cellular stress. Aberrant mitochondrial structures have long been observed in aging and age‐related diseases indicating that mitochondrial dynamics are compromised as cells age. However, the specific mechanisms by which aging affects mitochondrial dynamics and whether these changes are causally or casually associated with cellular and organismal aging is not clear. Here, we review recent studies that show specifically how mitochondrial fission, fusion, and trafficking are altered with age. We discuss factors that change with age to directly or indirectly influence mitochondrial dynamics while examining causal roles for altered mitochondrial dynamics in healthy aging and underlying functional outputs that might affect longevity. Lastly, we propose that altered mitochondrial dynamics might not just be a passive consequence of aging but might constitute an adaptive mechanism to mitigate age‐dependent cellular impairments and might be targeted to increase longevity and promote healthy aging.

    更新日期:2019-12-05
  • In vivo optochemical control of cell contractility at single‐cell resolution
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-30
    Deqing Kong; Zhiyi Lv; Matthias Häring; Benjamin Lin; Fred Wolf; Jörg Großhans
    更新日期:2019-12-05
  • Expression and phase separation potential of heterochromatin proteins during early mouse development
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-07
    Manuel Guthmann; Adam Burton; Maria‐Elena Torres‐Padilla
    更新日期:2019-12-05
  • Optogenetic inhibition of Delta reveals digital Notch signalling output during tissue differentiation
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-31
    Ranjith Viswanathan; Aleksandar Necakov; Mateusz Trylinski; Rohit Krishnan Harish; Daniel Krueger; Emilia Esposito; Francois Schweisguth; Pierre Neveu; Stefano De Renzis
    更新日期:2019-12-05
  • Apicomplexan F‐actin is required for efficient nuclear entry during host cell invasion
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-04
    Mario Del Rosario; Javier Periz; Georgios Pavlou; Oliver Lyth; Fernanda Latorre‐Barragan; Sujaan Das; Gurman S Pall; Johannes Felix Stortz; Leandro Lemgruber; Jamie A Whitelaw; Jake Baum; Isabelle Tardieux; Markus Meissner
    更新日期:2019-12-05
  • Essential roles of Windei and nuclear monoubiquitination of Eggless/SETDB1 in transposon silencing
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-02
    Ken Osumi; Kaoru Sato; Kensaku Murano; Haruhiko Siomi; Mikiko C Siomi
    更新日期:2019-12-05
  • ATF7IP regulates SETDB1 nuclear localization and increases its ubiquitination
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-02
    Takeshi Tsusaka; Chikako Shimura; Yoichi Shinkai
    更新日期:2019-12-05
  • Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-10
    Fumika Koyano; Koji Yamano; Hidetaka Kosako; Yoko Kimura; Mayumi Kimura; Yukio Fujiki; Keiji Tanaka; Noriyuki Matsuda
    更新日期:2019-12-05
  • Radial somatic F‐actin organization affects growth cone dynamics during early neuronal development
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-24
    Durga Praveen Meka; Robin Scharrenberg; Bing Zhao; Oliver Kobler; Theresa König; Irina Schaefer; Birgit Schwanke; Sergei Klykov; Melanie Richter; Dennis Eggert; Sabine Windhorst; Carlos G Dotti; Michael R Kreutz; Marina Mikhaylova; Froylan Calderon de Anda
    更新日期:2019-12-05
  • Mip6 binds directly to the Mex67 UBA domain to maintain low levels of Msn2/4 stress‐dependent mRNAs
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-03
    Manuel Martín‐Expósito; Maria‐Eugenia Gas; Nada Mohamad; Carme Nuño‐Cabanes; Ana Tejada‐Colón; Pau Pascual‐García; Lorena de la Fuente; Belén Chaves‐Arquero; Jonathan Merran; Jeffry Corden; Ana Conesa; José Manuel Pérez‐Cañadillas; Jerónimo Bravo; Susana Rodríguez‐Navarro
    更新日期:2019-12-05
  • SUMOylated SNF2PH promotes variant surface glycoprotein expression in bloodstream trypanosomes
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-06
    Andreu Saura; Paula A Iribarren; Domingo Rojas‐Barros; Jean M Bart; Diana López‐Farfán; Eduardo Andrés‐León; Isabel Vidal‐Cobo; Cordula Boehm; Vanina E Alvarez; Mark C Field; Miguel Navarro
    更新日期:2019-12-05
  • Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophages
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-21
    Kathrin Krause; Kylene Daily; Shady Estfanous; Kaitlin Hamilton; Asmaa Badr; Arwa Abu Khweek; Rana Hegazi; Midhun NK Anne; Brett Klamer; Xiaoli Zhang; Mikhail A Gavrilin; Vijay Pancholi; Amal O Amer
    更新日期:2019-12-05
  • TGF‐β‐activated lncRNA LINC00115 is a critical regulator of glioma stem‐like cell tumorigenicity
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-10
    Jianming Tang; Bo Yu; Yanxin Li; Weiwei Zhang; Angel A Alvarez; Bo Hu; Shi‐Yuan Cheng; Haizhong Feng
    更新日期:2019-12-05
  • ELAVL2‐directed RNA regulatory network drives the formation of quiescent primordial follicles
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-28
    Yuzuru Kato; Tokuko Iwamori; Youichirou Ninomiya; Takashi Kohda; Jyunko Miyashita; Mikiko Sato; Yumiko Saga
    更新日期:2019-12-05
  • Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
    EMBO Rep. (IF 8.383) Pub Date : 2019-10-31
    Amal M El‐Naggar; Syam Prakash Somasekharan; Yemin Wang; Hongwei Cheng; Gian Luca Negri; Melvin Pan; Xue Qi Wang; Alberto Delaidelli; Bo Rafn; Jordan Cran; Fan Zhang; Haifeng Zhang; Shane Colborne; Martin Gleave; Anna Mandinova; Nancy Kedersha; Christopher S Hughes; Didier Surdez; Olivier Delattre; Yuzhuo Wang; David G Huntsman; Gregg B Morin; Poul H Sorensen
    更新日期:2019-12-05
  • TMEM16A expression in cholinergic neurons of the medial habenula mediates anxiety‐related behaviors
    EMBO Rep. (IF 8.383) Pub Date : 2019-11-29
    Chang‐Hoon Cho; Sangjoon Lee; Ajung Kim; Oleg Yarishkin; Kanghyun Ryoo; Young‐Sun Lee; Hyun‐Gug Jung; Esther Yang; Da Yong Lee; Byeongjun Lee; Hyun Kim; Uhtaek Oh; Heh‐In Im; Eun Mi Hwang; Jae‐Yong Park
    更新日期:2019-11-30
  • The integrated stress response
    EMBO Rep. (IF 8.383) Pub Date : 2016-09-14
    Karolina Pakos‐Zebrucka; Izabela Koryga; Katarzyna Mnich; Mila Ljujic; Afshin Samali; Adrienne M Gorman

    In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro‐survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.

    更新日期:2019-11-18
  • Internet addiction disorder and youth
    EMBO Rep. (IF 8.383) Pub Date : 2014-01-07
    Patricia Wallace
    更新日期:2019-11-18
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