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Astrocyte allocation during brain development is controlled by Tcf4-mediated fate restriction. EMBO J. (IF 9.4) Pub Date : 2024-09-19 Yandong Zhang,Dan Li,Yuqun Cai,Rui Zou,Yilan Zhang,Xin Deng,Yafei Wang,Tianxiang Tang,Yuanyuan Ma,Feizhen Wu,Yunli Xie
Astrocytes in the brain exhibit regional heterogeneity contributing to regional circuits involved in higher-order brain functions, yet the mechanisms controlling their distribution remain unclear. Here, we show that the precise allocation of astrocytes to specific brain regions during development is achieved through transcription factor 4 (Tcf4)-mediated fate restriction based on their embryonic origin
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A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses. EMBO J. (IF 9.4) Pub Date : 2024-09-19 Masahiro Nagata,Yasmin Carvalho Schäfer,Laurens Wachsmuth,Manolis Pasparakis
Z-DNA-binding protein 1 (ZBP1) is an interferon-inducible sensor of Z-DNA and Z-RNA, which has emerged as a critical regulator of cell death and inflammation. ZBP1 binds Z-DNA and Z-RNA via its Zα domains, and signals by engaging RIPK3 and RIPK1 via its RIP homotypic interaction motifs (RHIMs). Here, we show that mice express an alternatively-spliced shorter ZBP1 isoform (ZBP1-S), which harbours the
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Acetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis. EMBO J. (IF 9.4) Pub Date : 2024-09-18 Xue Li,Xiangrong Li,Pengpeng Huang,Facai Zhang,Juanjuan K Du,Ying Kong,Ziqiang Shao,Xinxing Wu,Weijiao Fan,Houquan Tao,Chuanzan Zhou,Yan Shao,Yanling Jin,Meihua Ye,Yan Chen,Jong Deng,Jimin Shao,Jicheng Yue,Xiaju Cheng,Y Eugene Chinn
Activation of the Toll-like receptor 4 (TLR4) by bacterial endotoxins in macrophages plays a crucial role in the pathogenesis of sepsis. However, the mechanism underlying TLR4 activation in macrophages is still not fully understood. Here, we reveal that upon lipopolysaccharide (LPS) stimulation, lysine acetyltransferase CBP is recruited to the TLR4 signalosome complex leading to increased acetylation
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ER-phagy restrains inflammatory responses through its receptor UBAC2. EMBO J. (IF 9.4) Pub Date : 2024-09-16 Xing He,Haowei He,Zitong Hou,Zheyu Wang,Qinglin Shi,Tao Zhou,Yaoxing Wu,Yunfei Qin,Jun Wang,Zhe Cai,Jun Cui,Shouheng Jin
ER-phagy, a selective form of autophagic degradation of endoplasmic reticulum (ER) fragments, plays an essential role in governing ER homeostasis. Dysregulation of ER-phagy is associated with the unfolded protein response (UPR), which is a major clue for evoking inflammatory diseases. However, the molecular mechanism underpinning the connection between ER-phagy and disease remains poorly defined. Here
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Non-autophagic Golgi-LC3 lipidation facilitates TFE3 stress response against Golgi dysfunction. EMBO J. (IF 9.4) Pub Date : 2024-09-16 Jaemin Kang,Cathena Meiling Li,Namhoon Kim,Jongyeon Baek,Yong-Keun Jung
Lipidated ATG8/LC3 proteins are recruited to single membrane compartments as well as autophagosomes, supporting their functions. Although recent studies have shown that Golgi-LC3 lipidation follows Golgi damage, its molecular mechanism and function under Golgi stress remain unknown. Here, by combining DLK1 overexpression as a new strategy for induction of Golgi-specific LC3 lipidation, and the application
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Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling. EMBO J. (IF 9.4) Pub Date : 2024-09-16 Romain Vuillefroy de Silly,Laetitia Pericou,Bili Seijo,Isaac Crespo,Melita Irving
CD8 + T cells have critical roles in tumor control, but a range of factors in their microenvironment such as low pH can suppress their function. Here, we demonstrate that acidity restricts T-cell expansion mainly through impairing IL-2 responsiveness, lowers cytokine secretion upon re-activation, and reduces the cytolytic capacity of CD8 + T cells expressing low-affinity TCR. We further find decreased
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Decoupled transcript and protein concentrations ensure histone homeostasis in different nutrients. EMBO J. (IF 9.4) Pub Date : 2024-09-13 Dimitra Chatzitheodoridou,Daniela Bureik,Francesco Padovani,Kalyan V Nadimpalli,Kurt M Schmoller
To maintain protein homeostasis in changing nutrient environments, cells must precisely control the amount of their proteins, despite the accompanying changes in cell growth and biosynthetic capacity. As nutrients are major regulators of cell cycle length and progression, a particular challenge arises for the nutrient-dependent regulation of 'cell cycle genes', which are periodically expressed during
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TNFSF14+ natural killer cells prevent spontaneous abortion by restricting leucine-mediated decidual stromal cell senescence. EMBO J. (IF 9.4) Pub Date : 2024-09-11 Jia-Wei Shi,Zhen-Zhen Lai,Wen-Jie Zhou,Hui-Li Yang,Tao Zhang,Jian-Song Sun,Jian-Yuan Zhao,Ming-Qing Li
In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization
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Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks. EMBO J. (IF 9.4) Pub Date : 2024-09-11 Hilda Delgado de la Herran,Denis Vecellio Reane,Yiming Cheng,Máté Katona,Fabian Hosp,Elisa Greotti,Jennifer Wettmarshausen,Maria Patron,Hermine Mohr,Natalia Prudente de Mello,Margarita Chudenkova,Matteo Gorza,Safal Walia,Michael Sheng-Fu Feng,Anja Leimpek,Dirk Mielenz,Natalia S Pellegata,Thomas Langer,György Hajnóczky,Matthias Mann,Marta Murgia,Fabiana Perocchi
The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon
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Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production. EMBO J. (IF 9.4) Pub Date : 2024-09-11 Zhenlan Yao,Sangeetha Ramachandran,Serina Huang,Erin Kim,Yasaman Jami-Alahmadi,Prashant Kaushal,Mehdi Bouhaddou,James A Wohlschlegel,Melody Mh Li
Despite their role as innate sentinels, macrophages can serve as cellular reservoirs of chikungunya virus (CHIKV), a highly-pathogenic arthropod-borne alphavirus that has caused large outbreaks among human populations. Here, with the use of viral chimeras and evolutionary selection analysis, we define CHIKV glycoproteins E1 and E2 as critical for virion production in THP-1 derived human macrophages
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The global phosphorylation landscape of mouse oocytes during meiotic maturation. EMBO J. (IF 9.4) Pub Date : 2024-09-10 Hongzheng Sun,Longsen Han,Yueshuai Guo,Huiqing An,Bing Wang,Xiangzheng Zhang,Jiashuo Li,Yingtong Jiang,Yue Wang,Guangyi Sun,Shuai Zhu,Shoubin Tang,Juan Ge,Minjian Chen,Xuejiang Guo,Qiang Wang
Phosphorylation is a key post-translational modification regulating protein function and biological outcomes. However, the phosphorylation dynamics orchestrating mammalian oocyte development remains poorly understood. In the present study, we apply high-resolution mass spectrometry-based phosphoproteomics to obtain the first global in vivo quantification of mouse oocyte phosphorylation. Of more than
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Nitrogen signaling factor triggers a respiration-like gene expression program in fission yeast. EMBO J. (IF 9.4) Pub Date : 2024-09-10 Shin Ohsawa,Michaela Schwaiger,Vytautas Iesmantavicius,Rio Hashimoto,Hiromitsu Moriyama,Hiroaki Matoba,Go Hirai,Mikiko Sodeoka,Atsushi Hashimoto,Akihisa Matsuyama,Minoru Yoshida,Yoko Yashiroda,Marc Bühler
Microbes have evolved intricate communication systems that enable individual cells of a population to send and receive signals in response to changes in their immediate environment. In the fission yeast Schizosaccharomyces pombe, the oxylipin nitrogen signaling factor (NSF) is part of such communication system, which functions to regulate the usage of different nitrogen sources. Yet, the pathways and
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Heteroplasmy in action: tracking mtDNA segregation dynamics. EMBO J. (IF 9.4) Pub Date : 2024-09-10 Nitish Dua,Anjana Badrinarayanan
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Structural basis for the type I-F Cas8-HNH system. EMBO J. (IF 9.4) Pub Date : 2024-09-09 Xuzichao Li,Yanan Liu,Jie Han,Lingling Zhang,Zhikun Liu,Lin Wang,Shuqin Zhang,Qian Zhang,Pengyu Fu,Hang Yin,Hongtao Zhu,Heng Zhang
The Cas3 nuclease is utilized by canonical type I CRISPR-Cas systems for processive target DNA degradation, while a newly identified type I-F CRISPR variant employs an HNH nuclease domain from the natural fusion Cas8-HNH protein for precise target cleavage both in vitro and in human cells. Here, we report multiple cryo-electron microscopy structures of the type I-F Cas8-HNH system at different functional
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Histamine synthesis and transport are coupled in axon terminals via a dual quality control system. EMBO J. (IF 9.4) Pub Date : 2024-09-06 Lei Peng,Tao Wang
Monoamine neurotransmitters generated by de novo synthesis are rapidly transported and stored into synaptic vesicles at axon terminals. This transport is essential both for sustaining synaptic transmission and for limiting the toxic effects of monoamines. Here, synthesis of the monoamine histamine by histidine decarboxylase (HDC) and subsequent loading of histamine into synaptic vesicles are shown
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Structure of tetrameric forms of the serotonin-gated 5-HT3A receptor ion channel. EMBO J. (IF 9.4) Pub Date : 2024-09-04 Bianca Introini,Wenqiang Cui,Xiaofeng Chu,Yingyi Zhang,Ana Catarina Alves,Luise Eckhardt-Strelau,Sabrina Golusik,Menno Tol,Horst Vogel,Shuguang Yuan,Mikhail Kudryashev
Multimeric membrane proteins are produced in the endoplasmic reticulum and transported to their target membranes which, for ion channels, is typically the plasma membrane. Despite the availability of many fully assembled channel structures, our understanding of assembly intermediates, multimer assembly mechanisms, and potential functions of non-standard assemblies is limited. We demonstrate that the
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Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering. EMBO J. (IF 9.4) Pub Date : 2024-09-04 Paulina Kettel,Laura Marosits,Elena Spinetti,Michael Rechberger,Caterina Giannini,Philipp Radler,Isabell Niedermoser,Irmgard Fischer,Gijs A Versteeg,Martin Loose,Roberto Covino,G Elif Karagöz
Conserved signaling cascades monitor protein-folding homeostasis to ensure proper cellular function. One of the evolutionary conserved key players is IRE1, which maintains endoplasmic reticulum (ER) homeostasis through the unfolded protein response (UPR). Upon accumulation of misfolded proteins in the ER, IRE1 forms clusters on the ER membrane to initiate UPR signaling. What regulates IRE1 cluster
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A non-canonical repressor function of JUN restrains YAP activity and liver cancer growth. EMBO J. (IF 9.4) Pub Date : 2024-08-29 Yuliya Kurlishchuk,Anita Cindric Vranesic,Marco Jessen,Alexandra Kipping,Christin Ritter,KyungMok Kim,Paul Cramer,Björn von Eyss
Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effectors of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor
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STIC2 selectively binds ribosome-nascent chain complexes in the cotranslational sorting of Arabidopsis thylakoid proteins. EMBO J. (IF 9.4) Pub Date : 2024-08-27 Dominique S Stolle,Lena Osterhoff,Paul Treimer,Jan Lambertz,Marie Karstens,Jakob-Maximilian Keller,Ines Gerlach,Annika Bischoff,Beatrix Dünschede,Anja Rödiger,Christian Herrmann,Sacha Baginsky,Eckhard Hofmann,Reimo Zoschke,Ute Armbruster,Marc M Nowaczyk,Danja Schünemann
Chloroplast-encoded multi-span thylakoid membrane proteins are crucial for photosynthetic complexes, yet the coordination of their biogenesis remains poorly understood. To identify factors that specifically support the cotranslational biogenesis of the reaction center protein D1 of photosystem (PS) II, we generated and affinity-purified stalled ribosome-nascent chain complexes (RNCs) bearing D1 nascent
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Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence. EMBO J. (IF 9.4) Pub Date : 2024-08-27 Jia Xie,Zhao-Ning Lu,Shi-Hao Bai,Xiao-Fang Cui,He-Yuan Lian,Chen-Yi Xie,Na Wang,Lan Wang,Ze-Guang Han
Heterochromatin, a key component of the eukaryotic nucleus, is fundamental to the regulation of genome stability, gene expression and cellular functions. However, the factors and mechanisms involved in heterochromatin formation and maintenance still remain largely unknown. Here, we show that insulin receptor tyrosine kinase substrate (IRTKS), an I-BAR domain protein, is indispensable for constitutive
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Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy. EMBO J. (IF 9.4) Pub Date : 2024-08-27 James A Spudich,Neha Nandwani,Julien Robert-Paganin,Anne Houdusse,Kathleen M Ruppel
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CDK phosphorylation of Sfr1 downregulates Rad51 function in late-meiotic homolog invasions. EMBO J. (IF 9.4) Pub Date : 2024-08-22 Inés Palacios-Blanco,Lucía Gómez,María Bort,Nina Mayerová,Silvia Bágeľová Poláková,Cristina Martín-Castellanos
Meiosis is the developmental program that generates gametes. To produce healthy gametes, meiotic recombination creates reciprocal exchanges between each pair of homologous chromosomes that facilitate faithful chromosome segregation. Using fission yeast and biochemical, genetic, and cytological approaches, we have studied the role of CDK (cyclin-dependent kinase) in the control of Swi5-Sfr1, a Rad51-recombinase
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Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity. EMBO J. (IF 9.4) Pub Date : 2024-08-22 Man Xu,Jason J Hong,Xiyuan Zhang,Ming Sun,Xingyu Liu,Jeeyoun Kang,Hannah Stack,Wendy Fang,Haiyan Lei,Xavier Lacoste,Reona Okada,Raina Jung,Rosa Nguyen,Jack F Shern,Carol J Thiele,Zhihui Liu
Tumor cell heterogeneity defines therapy responsiveness in neuroblastoma (NB), a cancer derived from neural crest cells. NB consists of two primary subtypes: adrenergic and mesenchymal. Adrenergic traits predominate in NB tumors, while mesenchymal features becomes enriched post-chemotherapy or after relapse. The interconversion between these subtypes contributes to NB lineage plasticity, but the underlying
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DNA replication recruits a friend to overcome a challenging break-up. EMBO J. (IF 9.4) Pub Date : 2024-08-21 James M Dewar
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PCPE-1, a brown adipose tissue-derived cytokine, promotes obesity-induced liver fibrosis. EMBO J. (IF 9.4) Pub Date : 2024-08-19 Yung Ting Hsiao,Yohko Yoshida,Shujiro Okuda,Manabu Abe,Seiya Mizuno,Satoru Takahashi,Hironori Nakagami,Ryuichi Morishita,Kenya Kamimura,Shuji Terai,Tin May Aung,Ji Li,Takaaki Furihata,Jing Yuan Tang,Kenneth Walsh,Akihito Ishigami,Tohru Minamino,Ippei Shimizu
Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly
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Histone demethylase KDM2A recruits HCFC1 and E2F1 to orchestrate male germ cell meiotic entry and progression. EMBO J. (IF 9.4) Pub Date : 2024-08-19 Shenglei Feng,Yiqian Gui,Shi Yin,Xinxin Xiong,Kuan Liu,Jinmei Li,Juan Dong,Xixiang Ma,Shunchang Zhou,Bingqian Zhang,Shiyu Yang,Fengli Wang,Xiaoli Wang,Xiaohua Jiang,Shuiqiao Yuan
In mammals, the transition from mitosis to meiosis facilitates the successful production of gametes. However, the regulatory mechanisms that control meiotic initiation remain unclear, particularly in the context of complex histone modifications. Herein, we show that KDM2A, acting as a lysine demethylase targeting H3K36me3 in male germ cells, plays an essential role in modulating meiotic entry and progression
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Mouse models to investigate in situ cell fate decisions induced by p53. EMBO J. (IF 9.4) Pub Date : 2024-08-19 Elizabeth Lieschke,Annabella F Thomas,Andrew Kueh,Georgia K Atkin-Smith,Pedro L Baldoni,John E La Marca,Savannah Young,Allan Shuai Huang,Aisling M Ross,Lauren Whelan,Deeksha Kaloni,Lin Tai,Gordon K Smyth,Marco J Herold,Edwin D Hawkins,Andreas Strasser,Gemma L Kelly
Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic
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The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development. EMBO J. (IF 9.4) Pub Date : 2024-08-19 Muhammad Zahoor,Yanchen Dong,Marco Preussner,Veronika Reiterer,Sabrina Shameen Alam,Margot Haun,Utku Horzum,Yannick Frey,Renata Hajdu,Stephan Geley,Valerie Cormier-Daire,Florian Heyd,Loydie A Jerome-Majewska,Hesso Farhan
Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The
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An extrinsic motor directs chromatin loop formation by cohesin. EMBO J. (IF 9.4) Pub Date : 2024-08-19 Thomas M Guérin,Christopher Barrington,Georgii Pobegalov,Maxim I Molodtsov,Frank Uhlmann
The ring-shaped cohesin complex topologically entraps two DNA molecules to establish sister chromatid cohesion. Cohesin also shapes the interphase chromatin landscape with wide-ranging implications for gene regulation, and cohesin is thought to achieve this by actively extruding DNA loops without topologically entrapping DNA. The 'loop extrusion' hypothesis finds motivation from in vitro observations-whether
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CHC22 clathrin recruitment to the early secretory pathway requires two-site interaction with SNX5 and p115. EMBO J. (IF 9.4) Pub Date : 2024-08-19 Joshua Greig,George T Bates,Daowen I Yin,Kit Briant,Boris Simonetti,Peter J Cullen,Frances M Brodsky
The two clathrin isoforms, CHC17 and CHC22, mediate separate intracellular transport routes. CHC17 performs endocytosis and housekeeping membrane traffic in all cells. CHC22, expressed most highly in skeletal muscle, shuttles the glucose transporter GLUT4 from the ERGIC (endoplasmic-reticulum-to-Golgi intermediate compartment) directly to an intracellular GLUT4 storage compartment (GSC), from where
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EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-β. EMBO J. (IF 9.4) Pub Date : 2024-08-16 Xiaoyu Qian,Jin Cai,Yi Zhang,Shengqi Shen,Mingjie Wang,Shengzhi Liu,Xiang Meng,Junjiao Zhang,Zijian Ye,Shiqiao Qiu,Xiuying Zhong,Ping Gao
While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor
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Structure and replication of Pseudomonas aeruginosa phage JBD30. EMBO J. (IF 9.4) Pub Date : 2024-08-14 Lucie Valentová,Tibor Füzik,Jiří Nováček,Zuzana Hlavenková,Jakub Pospíšil,Pavel Plevka
Bacteriophages are the most abundant biological entities on Earth, but our understanding of many aspects of their lifecycles is still incomplete. Here, we have structurally analysed the infection cycle of the siphophage Casadabanvirus JBD30. Using its baseplate, JBD30 attaches to Pseudomonas aeruginosa via the bacterial type IV pilus, whose subsequent retraction brings the phage to the bacterial cell
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Gasdermin D cysteine residues synergistically control its palmitoylation-mediated membrane targeting and assembly. EMBO J. (IF 9.4) Pub Date : 2024-08-14 Eleonora Margheritis,Shirin Kappelhoff,John Danial,Nadine Gehle,Wladislaw Kohl,Rainer Kurre,Ayelén González Montoro,Katia Cosentino
Gasdermin D (GSDMD) executes the cell death program of pyroptosis by assembling into oligomers that permeabilize the plasma membrane. Here, by single-molecule imaging, we elucidate the yet unclear mechanism of Gasdermin D pore assembly and the role of cysteine residues in GSDMD oligomerization. We show that GSDMD preassembles at the membrane into dimeric and trimeric building blocks that can either
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Identification of BiP as a temperature sensor mediating temperature-induced germline sex reversal in C. elegans. EMBO J. (IF 9.4) Pub Date : 2024-08-12 Jing Shi,Danli Sheng,Jie Guo,Fangyuan Zhou,Shaofeng Wu,Hongyun Tang
Sex determination in animals is not only determined by karyotype but can also be modulated by environmental cues like temperature via unclear transduction mechanisms. Moreover, in contrast to earlier views that sex may exclusively be determined by either karyotype or temperature, recent observations suggest that these factors rather co-regulate sex, posing another mechanistic mystery. Here, we discovered
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Modular control of vertebrate axis segmentation in time and space. EMBO J. (IF 9.4) Pub Date : 2024-08-09 Ali Seleit,Ian Brettell,Tomas Fitzgerald,Carina Vibe,Felix Loosli,Joachim Wittbrodt,Kiyoshi Naruse,Ewan Birney,Alexander Aulehla
How the timing of development is linked to organismal size is a longstanding question. Although numerous studies have reported a correlation of temporal and spatial traits, the developmental or selective constraints underlying this link remain largely unexplored. We address this question by studying the periodic process of embryonic axis segmentation in-vivo in Oryzias fish. Interspecies comparisons
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RNA helicase SKIV2L limits antiviral defense and autoinflammation elicited by the OAS-RNase L pathway. EMBO J. (IF 9.4) Pub Date : 2024-08-07 Kun Yang,Beihua Dong,Abhishek Asthana,Robert H Silverman,Nan Yan
The OAS-RNase L pathway is one of the oldest innate RNA sensing pathways that leads to interferon (IFN) signaling and cell death. OAS recognizes viral RNA and then activates RNase L, which subsequently cleaves both cellular and viral RNA, creating "processed RNA" as an endogenous ligand that further triggers RIG-I-like receptor signaling. However, the IFN response and antiviral activity of the OAS-RNase
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Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level. EMBO J. (IF 9.4) Pub Date : 2024-08-05 Rodaria Roussou,Dirk Metzler,Francesco Padovani,Felix Thoma,Rebecca Schwarz,Boris Shraiman,Kurt M Schmoller,Christof Osman
Mitochondrial DNA (mtDNA) is present in multiple copies within cells and is required for mitochondrial ATP generation. Even within individual cells, mtDNA copies can differ in their sequence, a state known as heteroplasmy. The principles underlying dynamic changes in the degree of heteroplasmy remain incompletely understood, due to the inability to monitor this phenomenon in real time. Here, we employ
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PQBP3 prevents senescence by suppressing PSME3-mediated proteasomal Lamin B1 degradation. EMBO J. (IF 9.4) Pub Date : 2024-08-05 Yuki Yoshioka,Yong Huang,Xiaocen Jin,Kien Xuan Ngo,Tomohiro Kumaki,Meihua Jin,Saori Toyoda,Sumire Takayama,Maiko Inotsume,Kyota Fujita,Hidenori Homma,Toshio Ando,Hikari Tanaka,Hitoshi Okazawa
Senescence of nondividing neurons remains an immature concept, with especially the regulatory molecular mechanisms of senescence-like phenotypes and the role of proteins associated with neurodegenerative diseases in triggering neuronal senescence remaining poorly explored. In this study, we reveal that the nucleolar polyglutamine binding protein 3 (PQBP3; also termed NOL7), which has been linked to
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An ancient role for CYP73 monooxygenases in phenylpropanoid biosynthesis and embryophyte development. EMBO J. (IF 9.4) Pub Date : 2024-08-01 Samuel Knosp,Lucie Kriegshauser,Kanade Tatsumi,Ludivine Malherbe,Mathieu Erhardt,Gertrud Wiedemann,Bénédicte Bakan,Takayuki Kohchi,Ralf Reski,Hugues Renault
The phenylpropanoid pathway is one of the plant metabolic pathways most prominently linked to the transition to terrestrial life, but its evolution and early functions remain elusive. Here, we show that activity of the t-cinnamic acid 4-hydroxylase (C4H), the first plant-specific step in the pathway, emerged concomitantly with the CYP73 gene family in a common ancestor of embryophytes. Through structural
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Loss of Elp3 blocks intestinal tuft cell differentiation via an mTORC1-Atf4 axis. EMBO J. (IF 9.4) Pub Date : 2024-07-31 Caroline Wathieu,Arnaud Lavergne,Xinyi Xu,Marion Rolot,Ivan Nemazanyy,Kateryna Shostak,Najla El Hachem,Chloé Maurizy,Charlotte Leemans,Pierre Close,Laurent Nguyen,Christophe Desmet,Sylvia Tielens,Benjamin G Dewals,Alain Chariot
Intestinal tuft cells are critical for anti-helminth parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and
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LINE1 and its host: one cell's junk is another cell's treasure. EMBO J. (IF 9.4) Pub Date : 2024-07-29 John C Martinez,Andrei Seluanov,Vera Gorbunova
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Non-canonical NF-κB signaling limits the tolerogenic β-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies. EMBO J. (IF 9.4) Pub Date : 2024-07-25 Alvina Deka,Naveen Kumar,Swapnava Basu,Meenakshi Chawla,Namrata Bhattacharya,Sk Asif Ali,Bhawna,Upasna Madan,Shakti Kumar,Bhabatosh Das,Debarka Sengupta,Amit Awasthi,Soumen Basak
Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway
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Germline loss in C. elegans enhances longevity by disrupting adhesion between niche and stem cells. EMBO J. (IF 9.4) Pub Date : 2024-07-25 Meng Liu,Jiehui Chen,Guizhong Cui,Yumin Dai,Mengjiao Song,Chunyu Zhou,Qingyuan Hu,Qingxia Chen,Hongwei Wang,Wanli Chen,Jingdong Jackie Han,Guangdun Peng,Naihe Jing,Yidong Shen
Ageing and fertility are intertwined. Germline loss extends the lifespan in various organisms, termed gonadal longevity. However, the original longevity signal from the somatic gonad remains poorly understood. Here, we focused on the interaction between germline stem cells (GSCs) and their niche, the distal tip cells (DTCs), to explore the barely known longevity signal from the somatic gonad in C.
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Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling. EMBO J. (IF 9.4) Pub Date : 2024-07-23 Neuza Domingues,Steve Catarino,Beatriz Cristóvão,Lisa Rodrigues,Filomena A Carvalho,Maria João Sarmento,Mónica Zuzarte,Jani Almeida,Teresa Ribeiro-Rodrigues,Ânia Correia-Rodrigues,Fábio Fernandes,Paulo Rodrigues-Santos,Trond Aasen,Nuno C Santos,Viktor I Korolchuk,Teresa Gonçalves,Ira Milosevic,Nuno Raimundo,Henrique Girão
A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired.
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Handshaking for ultrafast endocytosis: Dynamin1xA and Endophilin A1 sealed the deal. EMBO J. (IF 9.4) Pub Date : 2024-07-23 Santiago López-Begines,Rafael Fernández-Chacón
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A common mechanism for recruiting the Rrm3 and RTEL1 accessory helicases to the eukaryotic replisome. EMBO J. (IF 9.4) Pub Date : 2024-07-22 Ottavia Olson,Simone Pelliciari,Emma D Heron,Tom D Deegan
The eukaryotic replisome is assembled around the CMG (CDC45-MCM-GINS) replicative helicase, which encircles the leading-strand DNA template at replication forks. When CMG stalls during DNA replication termination, or at barriers such as DNA-protein crosslinks on the leading strand template, a second helicase is deployed on the lagging strand template to support replisome progression. How these 'accessory'
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Ezrin, radixin, and moesin are dispensable for macrophage migration and cellular cortex mechanics. EMBO J. (IF 9.4) Pub Date : 2024-07-18 Perrine Verdys,Javier Rey Barroso,Adeline Girel,Joseph Vermeil,Martin Bergert,Thibaut Sanchez,Arnaud Métais,Thomas Mangeat,Elisabeth Bellard,Claire Bigot,Catherine Astarie-Dequeker,Arnaud Labrousse,Jean-Philippe Girard,Isabelle Maridonneau-Parini,Christel Vérollet,Frédéric Lagarrigue,Alba Diz-Muñoz,Julien Heuvingh,Matthieu Piel,Olivia du Roure,Véronique Le Cabec,Sébastien Carréno,Renaud Poincloux
The cellular cortex provides crucial mechanical support and plays critical roles during cell division and migration. The proteins of the ERM family, comprised of ezrin, radixin, and moesin, are central to these processes by linking the plasma membrane to the actin cytoskeleton. To investigate the contributions of the ERM proteins to leukocyte migration, we generated single and triple ERM knockout macrophages
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Reactive oxygen species activate the Drosophila TNF receptor Wengen for damage-induced regeneration. EMBO J. (IF 9.4) Pub Date : 2024-07-17 José Esteban-Collado,Mar Fernández-Mañas,Manuel Fernández-Moreno,Ignacio Maeso,Montserrat Corominas,Florenci Serras
Tumor necrosis factor receptors (TNFRs) control pleiotropic pro-inflammatory functions that range from apoptosis to cell survival. The ability to trigger a particular function will depend on the upstream cues, association with regulatory complexes, and downstream pathways. In Drosophila melanogaster, two TNFRs have been identified, Wengen (Wgn) and Grindelwald (Grnd). Although several reports associate
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A viral effector blocks the turnover of a plant NLR receptor to trigger a robust immune response. EMBO J. (IF 9.4) Pub Date : 2024-07-17 Chunli Wang,Min Zhu,Hao Hong,Jia Li,Chongkun Zuo,Yu Zhang,Yajie Shi,Suyu Liu,Haohua Yu,Yuling Yan,Jing Chen,Lingna Shangguan,Aiping Zhi,Rongzhen Chen,Karen Thulasi Devendrakumar,Xiaorong Tao
Plant intracellular nucleotide-binding and leucine-rich repeat immune receptors (NLRs) play a key role in activating a strong pathogen defense response. Plant NLR proteins are tightly regulated and accumulate at very low levels in the absence of pathogen effectors. However, little is known about how this low level of NLR proteins is able to induce robust immune responses upon recognition of pathogen
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Wengen's hidden powers: ROS triggers a TNFR-dependent tissue regenerative pathway in Drosophila. EMBO J. (IF 9.4) Pub Date : 2024-07-17 Ditte S Andersen,Julien Colombani
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TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes. EMBO J. (IF 9.4) Pub Date : 2024-07-16 Srijita Paul Chowdhuri,Benu Brata Das
Topoisomerase 1 (Top1) controls DNA topology, relieves DNA supercoiling during replication and transcription, and is critical for mitotic progression to the G1 phase. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1cc). Here, we identify CDK1-dependent phosphorylation of TDP1 at residue S61 during mitosis. A TDP1 variant defective for S61 phosphorylation
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Targeting neuronal epigenomes for brain rejuvenation. EMBO J. (IF 9.4) Pub Date : 2024-07-15 Sara Zocher
Aging is associated with a progressive decline of brain function, and the underlying causes and possible interventions to prevent this cognitive decline have been the focus of intense investigation. The maintenance of neuronal function over the lifespan requires proper epigenetic regulation, and accumulating evidence suggests that the deterioration of the neuronal epigenetic landscape contributes to
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Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23. EMBO J. (IF 9.4) Pub Date : 2024-07-15 Fenglian Liu,Tianyu Li,Huihui Gong,Fei Tian,Yan Bai,Haowei Wang,Chonglin Yang,Yang Li,Fei Guo,Sheng Liu,Qingfeng Chen
Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics that target the acetylcholine receptor ACR-23 and its homologs in nematodes. Here, we present cryo-electron microscopy structures of ACR-23 in apo, betaine-bound, and betaine- and monepantel-bound states
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Cytokinetic abscission in Toxoplasma gondii is governed by protein phosphatase 2A and the daughter cell scaffold complex. EMBO J. (IF 9.4) Pub Date : 2024-07-15 Jean-Baptiste Marq,Margaux Gosetto,Aline Altenried,Oscar Vadas,Bohumil Maco,Nicolas Dos Santos Pacheco,Nicolò Tosetti,Dominique Soldati-Favre,Gaëlle Lentini
Cytokinetic abscission marks the final stage of cell division, during which the daughter cells physically separate through the generation of new barriers, such as the plasma membrane or cell wall. While the contractile ring plays a central role during cytokinesis in bacteria, fungi and animal cells, the process diverges in Apicomplexa. In Toxoplasma gondii, two daughter cells are formed within the
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Antonello Covacci (1957-2023), a visionary and beautiful mind. EMBO J. (IF 9.4) Pub Date : 2024-07-15 Rino Rappuoli,Duccio Medini
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The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex. EMBO J. (IF 9.4) Pub Date : 2024-07-08 Sunaina Surana,David Villarroel-Campos,Elena R Rhymes,Maria Kalyukina,Chiara Panzi,Sergey S Novoselov,Federico Fabris,Sandy Richter,Marco Pirazzini,Giuseppe Zanotti,James N Sleigh,Giampietro Schiavo
Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. TeNT binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. While the extracellular matrix proteins nidogens are essential for TeNT binding, the molecular composition of its receptor complex remains unclear
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The caspase-activated DNase promotes cellular senescence. EMBO J. (IF 9.4) Pub Date : 2024-07-08 Aladin Haimovici,Valentin Rupp,Tarek Amer,Abdul Moeed,Arnim Weber,Georg Häcker
Cellular senescence is a response to many stressful insults. DNA damage is a consistent feature of senescent cells, but in many cases its source remains unknown. Here, we identify the cellular endonuclease caspase-activated DNase (CAD) as a critical factor in the initiation of senescence. During apoptosis, CAD is activated by caspases and cleaves the genomic DNA of the dying cell. The CAD DNase is
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Gut microbiota metabolite tyramine ameliorates high-fat diet-induced insulin resistance via increased Ca2+ signaling. EMBO J. (IF 9.4) Pub Date : 2024-07-04 Peng Ma,Yao Zhang,Youjie Yin,Saifei Wang,Shuxin Chen,Xueping Liang,Zhifang Li,Hansong Deng
The gut microbiota and their metabolites are closely linked to obesity-related diseases, such as type 2 diabetes, but their causal relationship and underlying mechanisms remain largely elusive. Here, we found that dysbiosis-induced tyramine (TA) suppresses high-fat diet (HFD)-mediated insulin resistance in both Drosophila and mice. In Drosophila, HFD increases cytosolic Ca2+ signaling in enterocytes
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LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response. EMBO J. (IF 9.4) Pub Date : 2024-07-01 Arianna Mangiavacchi,Gabriele Morelli,Sjur Reppe,Alfonso Saera-Vila,Peng Liu,Benjamin Eggerschwiler,Huoming Zhang,Dalila Bensaddek,Elisa A Casanova,Carolina Medina Gomez,Vid Prijatelj,Francesco Della Valle,Nazerke Atinbayeva,Juan Carlos Izpisua Belmonte,Fernando Rivadeneira,Paolo Cinelli,Kaare Morten Gautvik,Valerio Orlando
Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization
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Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism. EMBO J. (IF 9.4) Pub Date : 2024-06-27 Camila Cimadamore-Werthein,Martin S King,Denis Lacabanne,Eva Pyrihová,Stephany Jaiquel Baron,Edmund Rs Kunji
Members of the SLC25 mitochondrial carrier family link cytosolic and mitochondrial metabolism and support cellular maintenance and growth by transporting compounds across the mitochondrial inner membrane. Their monomeric or dimeric state and kinetic mechanism have been a matter of long-standing debate. It is believed by some that they exist as homodimers and transport substrates with a sequential kinetic