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A programmed decline in ribosome levels governs human early neurodevelopment 核糖体水平的程序性下降控制着人类早期神经发育
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-08-04 DOI: 10.1038/s41556-025-01708-8
Chunyang Ni, Yudong Wei, Barbara Vona, Dayea Park, Yulei Wei, Daniel A. Schmitz, Yi Ding, Masahiro Sakurai, Emily Ballard, Leijie Li, Yan Liu, Ashwani Kumar, Chao Xing, Shenlu Qin, Sangin Kim, Martina Foglizzo, Jianchao Zhao, Hyung-Goo Kim, Cumhur Ekmekci, Ehsan Ghayoor Karimiani, Shima Imannezhad, Fatemeh Eghbal, Reza Shervin Badv, Eva Maria Christina Schwaibold, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Zahra Metanat, Hosein Eslamiyeh, Ebtissal Khouj, Saleh Mohammed Nasser Alhajj, Aziza Chedrawi, Khushnooda Ramzan, Jamil A. Hashmi, Majed M. Alluqmani, Sulman Basit, Danai Veltra, Nikolaos M. Marinakis, Georgios Niotakis, Pelagia Vorgia, Christalena Sofocleous, Hane Lee, Won Chan Jeong, Muhammad Umair, Muhammad Bilal, César Augusto Pinheiro Ferreira Alves, Matthew Sieber, Michael Kruer, Henry Houlden, Fowzan S. Alkuraya, Elton Zeqiraj, Roger A. Greenberg, Can Cenik, Leqian Yu, Reza Maroofian, Jun Wu, Michael Buszczak
{"title":"A programmed decline in ribosome levels governs human early neurodevelopment","authors":"Chunyang Ni, Yudong Wei, Barbara Vona, Dayea Park, Yulei Wei, Daniel A. Schmitz, Yi Ding, Masahiro Sakurai, Emily Ballard, Leijie Li, Yan Liu, Ashwani Kumar, Chao Xing, Shenlu Qin, Sangin Kim, Martina Foglizzo, Jianchao Zhao, Hyung-Goo Kim, Cumhur Ekmekci, Ehsan Ghayoor Karimiani, Shima Imannezhad, Fatemeh Eghbal, Reza Shervin Badv, Eva Maria Christina Schwaibold, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Zahra Metanat, Hosein Eslamiyeh, Ebtissal Khouj, Saleh Mohammed Nasser Alhajj, Aziza Chedrawi, Khushnooda Ramzan, Jamil A. Hashmi, Majed M. Alluqmani, Sulman Basit, Danai Veltra, Nikolaos M. Marinakis, Georgios Niotakis, Pelagia Vorgia, Christalena Sofocleous, Hane Lee, Won Chan Jeong, Muhammad Umair, Muhammad Bilal, César Augusto Pinheiro Ferreira Alves, Matthew Sieber, Michael Kruer, Henry Houlden, Fowzan S. Alkuraya, Elton Zeqiraj, Roger A. Greenberg, Can Cenik, Leqian Yu, Reza Maroofian, Jun Wu, Michael Buszczak","doi":"10.1038/s41556-025-01708-8","DOIUrl":"https://doi.org/10.1038/s41556-025-01708-8","url":null,"abstract":"<p>Many neurodevelopmental defects are linked to genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. How reductions in ribosome biogenesis can result in tissue- and developmental-specific defects remains unclear. Here we describe variants in the ribosome biogenesis factor <i>AIRIM/C1orf109</i> that are primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic, single-cell RNA sequencing and single-organoid translation analyses, we identify a previously unappreciated drop in protein production during early brain development. We find that ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity suppresses the growth and developmental defects associated with <i>AIRIM/C1orf109</i> variants. This work provides evidence for the functional importance of regulated changes in global protein synthesis capacity during cellular differentiation.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"725 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux 细胞器吞噬受体的内在紊乱区域是可互换的,并控制细胞器碎片、er吞噬和有丝自噬通量
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-08-04 DOI: 10.1038/s41556-025-01728-4
Mikhail Rudinskiy, Carmela Galli, Andrea Raimondi, Maurizio Molinari
{"title":"The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux","authors":"Mikhail Rudinskiy, Carmela Galli, Andrea Raimondi, Maurizio Molinari","doi":"10.1038/s41556-025-01728-4","DOIUrl":"https://doi.org/10.1038/s41556-025-01728-4","url":null,"abstract":"<p>Organellophagy receptors control the generation and delivery of portions of their homing organelle to acidic degradative compartments to recycle nutrients, remove toxic or aged macromolecules and remodel the organelle upon physiologic or pathologic cues. How they operate is not understood. Here we show that organellophagy receptors are composed of a membrane-tethering module that controls organellar and suborganellar distribution and by a cytoplasmic intrinsically disordered region (IDR) with net cumulative negative charge that controls organelle fragmentation and displays an LC3-interacting region (LIR). The LIR is required for lysosomal delivery but is dispensable for organelle fragmentation. Endoplasmic reticulum (ER)-phagy receptors’ IDRs trigger DRP1-assisted mitochondrial fragmentation and mitophagy when transplanted at the outer mitochondrial membrane. Mitophagy receptors’ IDRs trigger ER fragmentation and ER-phagy when transplanted at the ER membrane. This offers an interesting example of function conservation on sequence divergency. Our results imply the possibility to control the integrity and activity of intracellular organelles by surface expression of organelle-targeted chimeras composed of an organelle-targeting module and an IDR module with net cumulative negative charge that, if it contains a LIR, eventually tags the organelle portions for lysosomal clearance.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"12 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pieces of the peroxisomal import puzzle 过氧化物酶体进口之谜的碎片
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-31 DOI: 10.1038/s41556-025-01727-5
Jianguo Wu, Min Zhuang
{"title":"Pieces of the peroxisomal import puzzle","authors":"Jianguo Wu, Min Zhuang","doi":"10.1038/s41556-025-01727-5","DOIUrl":"https://doi.org/10.1038/s41556-025-01727-5","url":null,"abstract":"Peroxisomes are single membrane-bound organelles containing numerous enzymes to perform metabolic functions. However, our view of peroxisomal protein import has remained incomplete. Two recent studies provide valuable insight to help explain the underlying molecular mechanisms of peroxisomal import.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"14 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
PEX39 facilitates the peroxisomal import of PTS2-containing proteins PEX39促进含有pts2蛋白的过氧化物酶体的输入
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-30 DOI: 10.1038/s41556-025-01711-z
Walter W. Chen, Tony A. Rodrigues, Daniel Wendscheck, Ana G. Pedrosa, Chendong Yang, Tânia Francisco, Till Möcklinghoff, Alexandros Zografakis, Bernardo Nunes-Silva, Reut E. Avraham, Ana R. Silva, Maria J. Ferreira, Hirak Das, Janet Koster, Simone Neuwirth, Julian Bender, Silke Oeljeklaus, Varun Sondhi, Christos Gatsogiannis, Maya Schuldiner, Einat Zalckvar, Kay Hofmann, Hans R. Waterham, Ralph J. DeBerardinis, Jorge E. Azevedo, Bettina Warscheid
{"title":"PEX39 facilitates the peroxisomal import of PTS2-containing proteins","authors":"Walter W. Chen, Tony A. Rodrigues, Daniel Wendscheck, Ana G. Pedrosa, Chendong Yang, Tânia Francisco, Till Möcklinghoff, Alexandros Zografakis, Bernardo Nunes-Silva, Reut E. Avraham, Ana R. Silva, Maria J. Ferreira, Hirak Das, Janet Koster, Simone Neuwirth, Julian Bender, Silke Oeljeklaus, Varun Sondhi, Christos Gatsogiannis, Maya Schuldiner, Einat Zalckvar, Kay Hofmann, Hans R. Waterham, Ralph J. DeBerardinis, Jorge E. Azevedo, Bettina Warscheid","doi":"10.1038/s41556-025-01711-z","DOIUrl":"https://doi.org/10.1038/s41556-025-01711-z","url":null,"abstract":"<p>Peroxisomes are metabolic organelles essential for human health. Defects in peroxisomal biogenesis proteins (also known as peroxins (PEXs)) cause devastating disease. PEX7 binds proteins containing a type 2 peroxisomal targeting signal (PTS2) to enable their import from the cytosol into peroxisomes, although many aspects of this process remain enigmatic. Utilizing in vitro assays, yeast and human cells, we show that PEX39, a previously uncharacterized protein, is a cytosolic peroxin that facilitates the import of PTS2-containing proteins by binding PEX7 and stabilizing its interaction with cargo proteins containing a PTS2. PEX39 and PEX13, a peroxisomal membrane translocon protein, both possess an (R/K)PWE motif necessary for PEX7 binding. Handover of PEX7 from PEX39 to PEX13 via these motifs provides a new paradigm for peroxisomal protein import and biogenesis. Collectively, this work reveals how PEX39 and (R/K)PWE motifs facilitate the import of PTS2-containing proteins and advances our understanding of peroxisomal disease.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"25 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery BNIP3/ nix -自噬起始的重构揭示了自噬机制的分层灵活性
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-25 DOI: 10.1038/s41556-025-01712-y
Elias Adriaenssens, Stefan Schaar, Annan S. I. Cook, Jan F. M. Stuke, Justyna Sawa-Makarska, Thanh Ngoc Nguyen, Xuefeng Ren, Martina Schuschnig, Julia Romanov, Grace Khuu, Louise Uoselis, Michael Lazarou, Gerhard Hummer, James H. Hurley, Sascha Martens
{"title":"Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery","authors":"Elias Adriaenssens, Stefan Schaar, Annan S. I. Cook, Jan F. M. Stuke, Justyna Sawa-Makarska, Thanh Ngoc Nguyen, Xuefeng Ren, Martina Schuschnig, Julia Romanov, Grace Khuu, Louise Uoselis, Michael Lazarou, Gerhard Hummer, James H. Hurley, Sascha Martens","doi":"10.1038/s41556-025-01712-y","DOIUrl":"https://doi.org/10.1038/s41556-025-01712-y","url":null,"abstract":"<p>Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI–ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, whereas FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with important implications for therapeutic interventions.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"1 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate 核外周通过抑制h3k9me2标记的基因和转座子来决定细胞的命运
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-22 DOI: 10.1038/s41556-025-01703-z
Harold C. Marin, Charlie Allen, Eric Simental, Eric W. Martin, Barbara Panning, Bassem Al-Sady, Abigail Buchwalter
{"title":"The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate","authors":"Harold C. Marin, Charlie Allen, Eric Simental, Eric W. Martin, Barbara Panning, Bassem Al-Sady, Abigail Buchwalter","doi":"10.1038/s41556-025-01703-z","DOIUrl":"https://doi.org/10.1038/s41556-025-01703-z","url":null,"abstract":"<p>Heterochromatic loci marked by histone H3 lysine 9 dimethylation (H3K9me2) are enriched at the nuclear periphery in metazoans, but the effect of spatial position on heterochromatin function has not been defined. Here we remove three nuclear lamins and the lamin B receptor (LBR) in mouse embryonic stem cells and show that heterochromatin detaches from the nuclear periphery. Mutant mouse embryonic stem cells sustain naive pluripotency and maintain H3K9me2 across the genome but cannot repress H3K9me2-marked genes or transposons. Further, mutant cells fail to differentiate into epiblast-like cells, a transition that requires the expansion of H3K9me2 across the genome. Mutant epiblast-like cells can silence naive pluripotency genes and activate epiblast-stage genes. However, H3K9me2 cannot repress markers of alternative fates, including primitive endoderm. We conclude that the lamins and LBR control the spatial position, dynamic remodelling and repressive capacity of H3K9me2-marked heterochromatin to shape cell fate decisions.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"228 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metabolic regulation of key developmental events during mammalian embryogenesis 哺乳动物胚胎发生过程中关键发育事件的代谢调节
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-22 DOI: 10.1038/s41556-025-01720-y
Yuyan Xu, Wei Xie, Jin Zhang
{"title":"Metabolic regulation of key developmental events during mammalian embryogenesis","authors":"Yuyan Xu, Wei Xie, Jin Zhang","doi":"10.1038/s41556-025-01720-y","DOIUrl":"https://doi.org/10.1038/s41556-025-01720-y","url":null,"abstract":"<p>Metabolic regulation is critical in embryonic development and influences key processes such as fertilization, zygotic genome activation, cell compaction, implantation, gastrulation and organ development. Here we explore the interplay between metabolism and embryonic development in the context of important sequential key embryonic events, highlighting the orchestration of developmental processes by various metabolites and signalling molecules. Key metabolites, including glucose, fatty acids and amino acids, act as modulators of developmental processes, while also serving as energy sources and building blocks for cellular structures. Understanding the intricate relationship between metabolism and embryogenesis may provide insights into developmental disorders and potential therapeutic interventions.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"4 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger TMEM65作为线粒体Na+/Ca2+交换器
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-21 DOI: 10.1038/s41556-025-01721-x
Jim Lu Zhang, Yu-Chen Chang, Po-Hsuan Lai, Han-I Yeh, Chen-Wei Tsai, Yu-Lun Huang, Tsung-Yun Liu, I-Chi Lee, North Foulon, Yan Xu, Bing Rao, Hsiu-Man Shih, Yung-Chi Tu, Andres V. Reyes, Shou-Ling Xu, Liang Feng, Ming-Feng Tsai
{"title":"TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger","authors":"Jim Lu Zhang, Yu-Chen Chang, Po-Hsuan Lai, Han-I Yeh, Chen-Wei Tsai, Yu-Lun Huang, Tsung-Yun Liu, I-Chi Lee, North Foulon, Yan Xu, Bing Rao, Hsiu-Man Shih, Yung-Chi Tu, Andres V. Reyes, Shou-Ling Xu, Liang Feng, Ming-Feng Tsai","doi":"10.1038/s41556-025-01721-x","DOIUrl":"https://doi.org/10.1038/s41556-025-01721-x","url":null,"abstract":"<p>Mitochondria export Ca<sup>2+</sup> via Na<sup>+</sup>/Ca<sup>2+</sup> exchange machinery (mito-NCX) to regulate intracellular Ca<sup>2+</sup> signalling and mitochondrial Ca<sup>2+</sup> homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na<sup>+</sup>/Ca<sup>2+</sup> exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca<sup>2+</sup> and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca<sup>2+</sup> dysregulation.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"13 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis ros介导的氧化- o - glcn酰化级联控制铁下垂
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-18 DOI: 10.1038/s41556-025-01722-w
Hemeng Zhang, Jialin Ma, Chunyan Hou, Xuehui Luo, Shiya Zhu, Yihan Peng, Changmin Peng, Ping Li, Heng Meng, Yuqi Xia, Zhinuo Jiang, Susree Modepalli, Anju Duttargi, Gary M. Kupfer, Mengjiao Cai, Heng Zhang, Junfeng Ma, Juanjuan Li, Suxia Han, Huadong Pei
{"title":"A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis","authors":"Hemeng Zhang, Jialin Ma, Chunyan Hou, Xuehui Luo, Shiya Zhu, Yihan Peng, Changmin Peng, Ping Li, Heng Meng, Yuqi Xia, Zhinuo Jiang, Susree Modepalli, Anju Duttargi, Gary M. Kupfer, Mengjiao Cai, Heng Zhang, Junfeng Ma, Juanjuan Li, Suxia Han, Huadong Pei","doi":"10.1038/s41556-025-01722-w","DOIUrl":"https://doi.org/10.1038/s41556-025-01722-w","url":null,"abstract":"<p>Reactive oxygen species (ROS) play a crucial role in lipid peroxidation and the initiation of ferroptosis, markedly affecting chemotherapeutic drug resistance. However, the mechanisms by which ROS function and are sensed remain poorly understood. In this study, we identified <i>O</i>-GlcNAc transferase (OGT), a key enzyme in protein <i>O</i>-GlcNAcylation, as a sensor for ROS during ferroptosis. The ROS-induced oxidation of OGT at C845 in its catalytic domain activates the enzyme. Once activated, OGT <i>O</i>-GlcNAcylates FOXK2, enhancing its interaction with importin α, which facilitates FOXK2’s nuclear translocation and binding to the SLC7A11 promoter region. This, in turn, boosts SLC7A11 transcription, thereby inhibiting ferroptosis. The elevated OGT–FOXK2–SLC7A11 axis contributes to tumorigenesis and resistance to chemoradiotherapy in hepatocellular carcinoma (HCC). Our findings elucidate a ROS-induced oxidation-<i>O</i>-GlcNAcylation cascade that integrates ROS signalling, <i>O</i>-GlcNAcylation, FOXK2-mediated SLC7A11 transcription and resistance to both ferroptosis and chemoradiotherapy.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"13 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Retraction Note: Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces 注:线粒体机械转导通过MIEF1协调核对力的反应
IF 21.3 1区 生物学
Nature Cell Biology Pub Date : 2025-07-16 DOI: 10.1038/s41556-025-01734-6
Patrizia Romani, Giada Benedetti, Martina Cusan, Mattia Arboit, Carmine Cirillo, Xi Wu, Georgia Rouni, Vassiliki Kostourou, Mariaceleste Aragona, Costanza Giampietro, Paolo Grumati, Graziano Martello, Sirio Dupont
{"title":"Retraction Note: Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces","authors":"Patrizia Romani, Giada Benedetti, Martina Cusan, Mattia Arboit, Carmine Cirillo, Xi Wu, Georgia Rouni, Vassiliki Kostourou, Mariaceleste Aragona, Costanza Giampietro, Paolo Grumati, Graziano Martello, Sirio Dupont","doi":"10.1038/s41556-025-01734-6","DOIUrl":"https://doi.org/10.1038/s41556-025-01734-6","url":null,"abstract":"<p>Retraction to: <i>Nature Cell Biology</i> (2024) 26:2046–2060 https://doi.org/10.1038/s41556-024-01527-3</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"24 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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