EMBO JournalPub Date : 2024-10-01Epub Date: 2024-09-04DOI: 10.1038/s44318-024-00207-0
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
{"title":"Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering.","authors":"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","doi":"10.1038/s44318-024-00207-0","DOIUrl":"10.1038/s44318-024-00207-0","url":null,"abstract":"<p><p>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 formation is not fully understood. Here, we show that the ER lumenal domain (LD) of human IRE1α forms biomolecular condensates in vitro. IRE1α LD condensates were stabilized both by binding to unfolded polypeptides as well as by tethering to model membranes, suggesting their role in assembling IRE1α into signaling-competent stable clusters. Molecular dynamics simulations indicated that weak multivalent interactions drive IRE1α LD clustering. Mutagenesis experiments identified disordered regions in IRE1α LD to control its clustering in vitro and in cells. Importantly, dysregulated clustering of IRE1α mutants led to defects in IRE1α signaling. Our results revealed that disordered regions in IRE1α LD control its clustering and suggest their role as a common strategy in regulating protein assembly on membranes.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4668-4698"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2024-10-01Epub Date: 2024-09-06DOI: 10.1038/s44318-024-00223-0
Lei Peng, Tao Wang
{"title":"Histamine synthesis and transport are coupled in axon terminals via a dual quality control system.","authors":"Lei Peng, Tao Wang","doi":"10.1038/s44318-024-00223-0","DOIUrl":"10.1038/s44318-024-00223-0","url":null,"abstract":"<p><p>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 to be physically and functionally coupled within Drosophila photoreceptor terminals. This process requires HDC anchoring to synaptic vesicles via interactions with N-ethylmaleimide-sensitive fusion protein 1 (NSF1). Disassociating HDC from synaptic vesicles disrupts visual synaptic transmission and causes somatic accumulation of histamine, which leads to retinal degeneration. We further identified a proteasome degradation system mediated by the E3 ubiquitin ligase, purity of essence (POE), which clears mislocalized HDC from the soma, thus eliminating the cytotoxic effects of histamine. Taken together, our results reveal a dual mechanism for translocation and degradation of HDC that ensures restriction of histamine synthesis to axonal terminals and at the same time rapid loading into synaptic vesicles. This is crucial for sustaining neurotransmission and protecting against cytotoxic monoamines.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4472-4491"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Gasdermin D cysteine residues synergistically control its palmitoylation-mediated membrane targeting and assembly.","authors":"Eleonora Margheritis, Shirin Kappelhoff, John Danial, Nadine Gehle, Wladislaw Kohl, Rainer Kurre, Ayelén González Montoro, Katia Cosentino","doi":"10.1038/s44318-024-00190-6","DOIUrl":"10.1038/s44318-024-00190-6","url":null,"abstract":"<p><p>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 be inserted into the membrane, or further assemble into higher-order oligomers prior to insertion into the membrane. The GSDMD residues Cys39, Cys57, and Cys192 are the only relevant cysteines involved in GSDMD oligomerization. S-palmitoylation of Cys192, combined with the presence of negatively-charged lipids, controls GSDMD membrane targeting. Simultaneous Cys39/57/192-to-alanine (Ala) mutations, but not Ala mutations of Cys192 or the Cys39/57 pair individually, completely abolish GSDMD insertion into artificial membranes as well as into the plasma membrane. Finally, either Cys192 or the Cys39/Cys57 pair are sufficient to enable formation of GSDMD dimers/trimers, but they are all required for functional higher-order oligomer formation. Overall, our study unveils a cooperative role of Cys192 palmitoylation-mediated membrane binding and Cys39/57/192-mediated oligomerization in GSDMD pore assembly. This study supports a model in which Gasdermin D oligomerization relies on a two-step mechanism mediated by specific cysteine residues.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4274-4297"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2024-10-01Epub Date: 2024-08-27DOI: 10.1038/s44318-024-00212-3
Jia Xie, Zhao-Ning Lu, Shi-Hao Bai, Xiao-Fang Cui, He-Yuan Lian, Chen-Yi Xie, Na Wang, Lan Wang, Ze-Guang Han
{"title":"Heterochromatin formation and remodeling by IRTKS condensates counteract cellular senescence.","authors":"Jia Xie, Zhao-Ning Lu, Shi-Hao Bai, Xiao-Fang Cui, He-Yuan Lian, Chen-Yi Xie, Na Wang, Lan Wang, Ze-Guang Han","doi":"10.1038/s44318-024-00212-3","DOIUrl":"10.1038/s44318-024-00212-3","url":null,"abstract":"<p><p>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 heterochromatin formation via liquid‒liquid phase separation (LLPS). In particular, IRTKS droplets can infiltrate heterochromatin condensates composed of HP1α and diverse DNA-bound nucleosomes. IRTKS can stabilize HP1α by recruiting the E2 ligase Ubc9 to SUMOylate HP1α, which enables it to form larger phase-separated droplets than unmodified HP1α. Furthermore, IRTKS deficiency leads to loss of heterochromatin, resulting in genome-wide changes in chromatin accessibility and aberrant transcription of repetitive DNA elements. This leads to activation of cGAS-STING pathway and type-I interferon (IFN-I) signaling, as well as to the induction of cellular senescence and senescence-associated secretory phenotype (SASP) responses. Collectively, our findings establish a mechanism by which IRTKS condensates consolidate constitutive heterochromatin, revealing an unexpected role of IRTKS as an epigenetic mediator of cellular senescence.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4542-4577"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2024-10-01Epub Date: 2024-09-16DOI: 10.1038/s44318-024-00209-y
William Teale, Daniel Klimmeck
{"title":"Metabolism: getting things right!","authors":"William Teale, Daniel Klimmeck","doi":"10.1038/s44318-024-00209-y","DOIUrl":"10.1038/s44318-024-00209-y","url":null,"abstract":"","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4443"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2024-10-01Epub Date: 2024-08-14DOI: 10.1038/s44318-024-00194-2
Luca Cirillo, Rose Young, Sapthaswaran Veerapathiran, Annalisa Roberti, Molly Martin, Azzah Abubacar, Camilla Perosa, Catherine Coates, Reyhan Muhammad, Theodoros I Roumeliotis, Jyoti S Choudhary, Claudio Alfieri, Jonathon Pines
{"title":"Spatial control of the APC/C ensures the rapid degradation of cyclin B1.","authors":"Luca Cirillo, Rose Young, Sapthaswaran Veerapathiran, Annalisa Roberti, Molly Martin, Azzah Abubacar, Camilla Perosa, Catherine Coates, Reyhan Muhammad, Theodoros I Roumeliotis, Jyoti S Choudhary, Claudio Alfieri, Jonathon Pines","doi":"10.1038/s44318-024-00194-2","DOIUrl":"10.1038/s44318-024-00194-2","url":null,"abstract":"<p><p>The proper control of mitosis depends on the ubiquitin-mediated degradation of the right mitotic regulator at the right time. This is effected by the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase that is regulated by the Spindle Assembly Checkpoint (SAC). The SAC prevents the APC/C from recognising Cyclin B1, the essential anaphase and cytokinesis inhibitor, until all chromosomes are attached to the spindle. Once chromosomes are attached, Cyclin B1 is rapidly degraded to enable chromosome segregation and cytokinesis. We have a good understanding of how the SAC inhibits the APC/C, but relatively little is known about how the APC/C recognises Cyclin B1 as soon as the SAC is turned off. Here, by combining live-cell imaging, in vitro reconstitution biochemistry, and structural analysis by cryo-electron microscopy, we provide evidence that the rapid recognition of Cyclin B1 in metaphase requires spatial regulation of the APC/C. Using fluorescence cross-correlation spectroscopy, we find that Cyclin B1 and the APC/C primarily interact at the mitotic apparatus. We show that this is because Cyclin B1, like the APC/C, binds to nucleosomes, and identify an 'arginine-anchor' in the N-terminus as necessary and sufficient for binding to the nucleosome. Mutating the arginine anchor on Cyclin B1 reduces its interaction with the APC/C and delays its degradation: cells with the mutant, non-nucleosome-binding Cyclin B1 become aneuploid, demonstrating the physiological relevance of our findings. Together, our data demonstrate that mitotic chromosomes promote the efficient interaction between Cyclin B1 and the APC/C to ensure the timely degradation of Cyclin B1 and genomic stability.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4324-4355"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2024-10-01Epub Date: 2024-08-16DOI: 10.1038/s44318-024-00201-6
Xiaoyu Qian, Jin Cai, Yi Zhang, Shengqi Shen, Mingjie Wang, Shengzhi Liu, Xiang Meng, Junjiao Zhang, Zijian Ye, Shiqiao Qiu, Xiuying Zhong, Ping Gao
{"title":"EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-β.","authors":"Xiaoyu Qian, Jin Cai, Yi Zhang, Shengqi Shen, Mingjie Wang, Shengzhi Liu, Xiang Meng, Junjiao Zhang, Zijian Ye, Shiqiao Qiu, Xiuying Zhong, Ping Gao","doi":"10.1038/s44318-024-00201-6","DOIUrl":"10.1038/s44318-024-00201-6","url":null,"abstract":"<p><p>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 immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-b, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8<sup>+</sup> T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4248-4273"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2024-10-01Epub Date: 2024-08-27DOI: 10.1038/s44318-024-00176-4
Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll
{"title":"A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.","authors":"Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll","doi":"10.1038/s44318-024-00176-4","DOIUrl":"10.1038/s44318-024-00176-4","url":null,"abstract":"<p><p>Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4492-4521"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO JournalPub Date : 2024-10-01Epub Date: 2024-08-27DOI: 10.1038/s44318-024-00211-4
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
{"title":"STIC2 selectively binds ribosome-nascent chain complexes in the cotranslational sorting of Arabidopsis thylakoid proteins.","authors":"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","doi":"10.1038/s44318-024-00211-4","DOIUrl":"10.1038/s44318-024-00211-4","url":null,"abstract":"<p><p>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 chains. Stalled RNCs translating the soluble ribosomal subunit uS2c were used for comparison. Quantitative tandem-mass spectrometry of the purified RNCs identified around 140 proteins specifically associated with D1 RNCs, mainly involved in protein and cofactor biogenesis, including chlorophyll biosynthesis, and other metabolic pathways. Functional analysis of STIC2, a newly identified D1 RNC interactor, revealed its cooperation with chloroplast protein SRP54 in the de novo biogenesis and repair of D1, and potentially other cotranslationally-targeted reaction center subunits of PSII and PSI. The primary binding interface between STIC2 and the thylakoid insertase Alb3 and its homolog Alb4 was mapped to STIC2's β-sheet region, and the conserved Motif III in the C-terminal regions of Alb3/4.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4699-4719"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Histone demethylase KDM2A recruits HCFC1 and E2F1 to orchestrate male germ cell meiotic entry and progression.","authors":"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","doi":"10.1038/s44318-024-00203-4","DOIUrl":"10.1038/s44318-024-00203-4","url":null,"abstract":"<p><p>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. Conditional deletion of Kdm2a in mouse pre-meiotic germ cells results in complete male sterility, with spermatogenesis ultimately arrested at the zygotene stage of meiosis. KDM2A deficiency disrupts H3K36me2/3 deposition in c-KIT<sup>+</sup> germ cells, characterized by a reduction in H3K36me2 but a dramatic increase in H3K36me3. Furthermore, KDM2A recruits the transcription factor E2F1 and its co-factor HCFC1 to the promoters of key genes required for meiosis entry and progression, such as Stra8, Meiosin, Spo11, and Sycp1. Collectively, our study unveils an essential role for KDM2A in mediating H3K36me2/3 deposition and controlling the programmed gene expression necessary for the transition from mitosis to meiosis during spermatogenesis.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4197-4227"},"PeriodicalIF":9.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}