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Heat stress responses mediated by N6-methyladenine DNA methylation in maize. 玉米n6 -甲基腺嘌呤DNA甲基化介导的热胁迫反应
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-28 DOI: 10.1016/j.celrep.2025.116058
Weijun Guo, Liang Le, Daolei Zhang, Ziwei Wei, Yifan Wang, Yue Wu, Hada Wuriyanghan, Xiaofeng Gu, Li Pu
{"title":"Heat stress responses mediated by N6-methyladenine DNA methylation in maize.","authors":"Weijun Guo, Liang Le, Daolei Zhang, Ziwei Wei, Yifan Wang, Yue Wu, Hada Wuriyanghan, Xiaofeng Gu, Li Pu","doi":"10.1016/j.celrep.2025.116058","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116058","url":null,"abstract":"<p><p>N6-methyladenine (6mA) plays an important role in eukaryotic development and stress responses, yet its function under heat stress (HS) in crops remains unclear. Here, we show that 6mA dynamics in two maize inbred lines, B73 and Mo17, correlate with their responses to HS. Genome-wide 6mA profiling reveals enrichment in promoters, intergenic regions, and transposable elements (TEs), with inverse correlation with gene/TE expression. Upon HS, heat-tolerant plants show elevated 6mA levels, with differential 6mA patterning on key HS-related genes underlying thermotolerance variation between B73 and Mo17. We identified ZmALKBH1 as a 6mA demethylase, and its mutation enhances HS tolerance. A deep learning model based on 6mA methylomes of B73 and Mo17 accurately predicts and experimentally validates 6mA distribution and HS response in additional W22 and B104 lines. These findings uncover the role of 6mA in transcriptional regulation of crop stress adaptation and offer potential targets for improving thermotolerance in maize.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116058"},"PeriodicalIF":6.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741322","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 spatiotemporal atlas of mouse gastrulation and early organogenesis to explore axial patterning and project in vitro models onto in vivo space. 小鼠原肠胚形成和早期器官发生的时空图谱,探索轴向模式,并将体外模型投射到体内空间。
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-28 DOI: 10.1016/j.celrep.2025.116047
Luke T G Harland, Tim Lohoff, Noushin Koulena, Nico Pierson, Constantin Pape, Farhan Ameen, Jonathan Griffiths, Bart Theeuwes, Nicola K Wilson, Anna Kreshuk, Wolf Reik, Jennifer Nichols, Long Cai, John C Marioni, Berthold Göttgens, Shila Ghazanfar
{"title":"A spatiotemporal atlas of mouse gastrulation and early organogenesis to explore axial patterning and project in vitro models onto in vivo space.","authors":"Luke T G Harland, Tim Lohoff, Noushin Koulena, Nico Pierson, Constantin Pape, Farhan Ameen, Jonathan Griffiths, Bart Theeuwes, Nicola K Wilson, Anna Kreshuk, Wolf Reik, Jennifer Nichols, Long Cai, John C Marioni, Berthold Göttgens, Shila Ghazanfar","doi":"10.1016/j.celrep.2025.116047","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116047","url":null,"abstract":"<p><p>During gastrulation, mouse epiblast cells form the three germ layers that establish the body plan and initiate organogenesis. While single-cell atlases have advanced our understanding of lineage diversification, spatial aspects of differentiation remain poorly defined. Here, we applied spatial transcriptomics to mouse embryos at embryonic (E) E7.25 and E7.5 days and integrated these data with existing E8.5 spatial and E6.5-E9.5 single-cell RNA-seq atlases. This resulted in a spatiotemporal atlas of over 150,000 cells with 82 refined cell-type annotations. The resource enables exploration of gene expression dynamics across anterior-posterior and dorsal-ventral axes, uncovering spatial logic guiding mesodermal fate decisions in the primitive streak. We also developed a computational pipeline to project additional single-cell datasets into this framework for comparative analysis. Freely accessible through an interactive web portal, this atlas offers a valuable tool for the developmental and stem cell biology communities to investigate mouse embryogenesis in a spatial and temporal context.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116047"},"PeriodicalIF":6.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741321","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
Neuroimmune axis in gastrointestinal cancers: From mechanisms to therapeutic breakthrough. 胃肠道肿瘤的神经免疫轴:从机制到治疗突破。
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-28 DOI: 10.1016/j.celrep.2025.116059
Yixuan Zhang, Jintian Chen, Yiwei Zhou, Yanjun Jiang, Jielun Hu, Xiaodong Liu, Jingying Zhou
{"title":"Neuroimmune axis in gastrointestinal cancers: From mechanisms to therapeutic breakthrough.","authors":"Yixuan Zhang, Jintian Chen, Yiwei Zhou, Yanjun Jiang, Jielun Hu, Xiaodong Liu, Jingying Zhou","doi":"10.1016/j.celrep.2025.116059","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116059","url":null,"abstract":"<p><p>Accumulating evidence has demonstrated that tumor cells can co-opt the nervous and immune systems to facilitate their growth, progression, and metastasis. Tumor innervation has been reported to regulate cancer development either directly or indirectly by modulating immune evasion through the neuroimmune axis. Building on insights into the mechanisms of cancer-neuroimmune interactions, attention is turning to developing novel therapeutics by repurposing neuropsychiatric drugs or using neuromodulation. Given the rich innervation of the gastrointestinal (GI) tract and its accessory organs, we summarize the current understanding of neuroimmune networks in GI cancers, focusing on the most recent updates of neurotransmitter-receptor pathways and tumor-innervating nociceptors. Additionally, we discuss the underlying mechanisms of these pathways and explore their therapeutic implications, which may potentially lead to new approaches for combinatory immunotherapies in GI cancers.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116059"},"PeriodicalIF":6.9,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741323","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 trans-kingdom T6SS RNase effector targeting both prokaryotic and host cells for pathogenesis. 针对原核细胞和宿主细胞的跨界T6SS RNase效应物。
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-26 DOI: 10.1016/j.celrep.2025.116074
Yudi Wang, Yongdong Li, Zonglan Yu, Wenjing Zhang, Zhaorui Ren, Hongyun Zhang, Lu Xiao, Shengzhi Guo, Jinfang Zhou, Lingfang Zhu, Changfu Li, Lei Xu, Yao Wang, Yi Chen, Xihui Shen, Yantao Yang
{"title":"A trans-kingdom T6SS RNase effector targeting both prokaryotic and host cells for pathogenesis.","authors":"Yudi Wang, Yongdong Li, Zonglan Yu, Wenjing Zhang, Zhaorui Ren, Hongyun Zhang, Lu Xiao, Shengzhi Guo, Jinfang Zhou, Lingfang Zhu, Changfu Li, Lei Xu, Yao Wang, Yi Chen, Xihui Shen, Yantao Yang","doi":"10.1016/j.celrep.2025.116074","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116074","url":null,"abstract":"<p><p>The bacterial type VI secretion system (T6SS) mediates interactions with neighboring cells or the environment by secreting various effectors, yet T6SS RNase effectors have barely been studied. Here, we report a multifunctional trans-kingdom T6SS RNase effector, TseR, from Yersinia pseudotuberculosis (Yptb). TseR, an Ntox44 domain-containing effector secreted by T6SS-3, is a divalent cation-dependent RNase that preferentially cleaves single-stranded RNA, which can be inhibited by the cognate immunity protein TsiR. TseR mediated both contact-dependent and contact-independent T6SS killing of bacteria, with OmpC facilitating its entry into target cells during contact-independent killing. The global cleavage targets of TseR in Escherichia coli were identified via RNA-seq analysis. During infections, TseR facilitated pathogenicity by altering the gut microbiome and directly targeting eukaryotic host cells. This study provides valuable insights into the roles of the T6SS RNase effector and the Ntox44 family protein in bacterial competition and bacteria-host interactions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116074"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728310","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
Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling. 葡萄糖激活的JMJD1A通过α-酮戊二酸依赖的染色质重塑驱动内脏脂肪形成。
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-26 DOI: 10.1016/j.celrep.2025.116060
Chenxu Yang, Makoto Arai, Eko Fuji Ariyanto, Ji Zhang, Debby Mirani Lubis, Ryo Ito, Shiyu Xie, Mio Nitta, Fuka Kawashima, Tomofumi Ishitsuka, Chaoran Yang, Tomohiro Suzuki, Tetsuro Komatsu, Hina Sagae, Hitomi Jin, Hiroki Takahashi, Eri Kobayashi, Yuchen Wei, Bohao Liu, Hyunmi Choi, Youichiro Wada, Toshiya Tanaka, Tsuyoshi Osawa, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Makoto Tachibana, Yoichi Shinkai, Takeshi Inagaki, Tomoyoshi Soga, Timothy F Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai
{"title":"Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling.","authors":"Chenxu Yang, Makoto Arai, Eko Fuji Ariyanto, Ji Zhang, Debby Mirani Lubis, Ryo Ito, Shiyu Xie, Mio Nitta, Fuka Kawashima, Tomofumi Ishitsuka, Chaoran Yang, Tomohiro Suzuki, Tetsuro Komatsu, Hina Sagae, Hitomi Jin, Hiroki Takahashi, Eri Kobayashi, Yuchen Wei, Bohao Liu, Hyunmi Choi, Youichiro Wada, Toshiya Tanaka, Tsuyoshi Osawa, Hiroshi Kimura, Tatsuhiko Kodama, Hiroyuki Aburatani, Makoto Tachibana, Yoichi Shinkai, Takeshi Inagaki, Tomoyoshi Soga, Timothy F Osborne, Takeshi Yoneshiro, Yoshihiro Matsumura, Juro Sakai","doi":"10.1016/j.celrep.2025.116060","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116060","url":null,"abstract":"<p><p>Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116060"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728311","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
Metal-induced nanoscale clusterization initiates protein liquid-liquid phase separation. 金属诱导的纳米级簇化引发了蛋白质的液-液相分离。
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-26 DOI: 10.1016/j.celrep.2025.116067
Sijia Xiang, Zhuanghao Hou, Yu Wang, Yang Yang, Hongze Hu, Chang Yin, Guangming Huang, Kaiming Cao, Yangzhong Liu
{"title":"Metal-induced nanoscale clusterization initiates protein liquid-liquid phase separation.","authors":"Sijia Xiang, Zhuanghao Hou, Yu Wang, Yang Yang, Hongze Hu, Chang Yin, Guangming Huang, Kaiming Cao, Yangzhong Liu","doi":"10.1016/j.celrep.2025.116067","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116067","url":null,"abstract":"<p><p>Liquid-liquid phase separation (LLPS) of biomolecules is a crucial mechanism in regulating cellular functions through dynamic formation of membrane-less organelles. The assembly of nucleation seeds is a key step that triggers LLPS; however, it is challenging to precisely study its assembly mechanism due to the complexity of the condensation process. Recently, metal ions have been found to play important roles in inducing LLPS. To elucidate the assembling mechanism, a small ubiquitin-like modifier (SUMO) protein was employed as a model protein to study metal-induced condensation. The results indicate that SUMO possesses two weak Cu(II)-binding sites across the protein surface, enabling intermolecular bridging among SUMO molecules. The formation of assembling seeds is confirmed by mass photometry analysis, showing the Cu(II)-induced dynamic clusterization of SUMO at nanoscale. Increasing the Cu(II) binding affinity of SUMO significantly promotes the protein condensation, underscoring the pivotal role of Cu(II) coordination in LLPS. This work provides insights into the protein assembly mechanism through non-specific intermolecular metal coordination.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116067"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728313","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
Identification and engineering of potent bispecific antibodies that protect against herpes simplex virus recurrent disease. 预防单纯疱疹病毒复发性疾病的强效双特异性抗体的鉴定和工程设计。
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-26 DOI: 10.1016/j.celrep.2025.116063
Chingwei V Lee, Hector Viadiu, Apurva Kalamkar, David I Bernstein, Andrew Pae, Xinchao Yu, Sylvia Wong, Fernando J Bravo, Sheng Ding, Elbert Seto, Magdeleine Hung, Yu Yu, Weimei Xing, Giuseppe A Papalia, Wei Kan, Brian Carr, Majlinda Thomas, Leah Tong, Priyanka Desai, Nadine Jarrousse, Alexandre Mercier, Meghan M Holdorf, Simon P Fletcher, Emma Abernathy
{"title":"Identification and engineering of potent bispecific antibodies that protect against herpes simplex virus recurrent disease.","authors":"Chingwei V Lee, Hector Viadiu, Apurva Kalamkar, David I Bernstein, Andrew Pae, Xinchao Yu, Sylvia Wong, Fernando J Bravo, Sheng Ding, Elbert Seto, Magdeleine Hung, Yu Yu, Weimei Xing, Giuseppe A Papalia, Wei Kan, Brian Carr, Majlinda Thomas, Leah Tong, Priyanka Desai, Nadine Jarrousse, Alexandre Mercier, Meghan M Holdorf, Simon P Fletcher, Emma Abernathy","doi":"10.1016/j.celrep.2025.116063","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116063","url":null,"abstract":"<p><p>Herpes simplex virus (HSV) causes lifelong infections, including oral and genital herpes. There is no vaccine, and current antivirals are only partially effective at reducing symptoms and transmission. Therapeutic antibodies offer a potentially long-acting treatment option, although efforts to pursue this have been limited. We performed an alpaca immunization campaign and discovered high-affinity antibodies that both neutralized and completely blocked cell-to-cell spread (CCS), a key mechanism by which HSV evades neutralizing antibodies. Unexpectedly, we found that engineering antibodies into a bispecific format targeting two viral glycoproteins dramatically increased antiviral potency. Solving the structures of three antibodies using cryo-electron microscopy (cryo-EM) revealed a mechanistic understanding of how the bispecific format could enhance potency. Lastly, these bispecific antibodies significantly reduced lesion development in the guinea pig model of genital herpes, demonstrating that delayed dosing after latency establishment can reduce disease and confirming their potential as a transformative treatment option.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116063"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728312","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 Hippo pathway kinase MST1 mediates a feedback loop to maintain NLRP3 inflammasome homeostasis. Hippo通路激酶MST1介导一个反馈回路来维持NLRP3炎性小体的稳态。
IF 6.9 1区 生物学
Cell reports Pub Date : 2025-07-26 DOI: 10.1016/j.celrep.2025.116076
Xiawei Huang, Jiahui Wang, Yao Liu, Huimin Pan, Kewei Zheng, Bo Liu
{"title":"The Hippo pathway kinase MST1 mediates a feedback loop to maintain NLRP3 inflammasome homeostasis.","authors":"Xiawei Huang, Jiahui Wang, Yao Liu, Huimin Pan, Kewei Zheng, Bo Liu","doi":"10.1016/j.celrep.2025.116076","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116076","url":null,"abstract":"<p><p>Inflammasomes play pivotal roles in inflammatory responses. However, their activity must be tightly controlled to prevent overactivation and subsequent inflammatory diseases. Negative feedback loops represent a general mechanism to maintain signaling homeostasis, yet the mechanisms by which inflammasomes employ this process to prevent overactivation remain poorly understood. Here, we identify a negative feedback loop mediated by the Hippo pathway kinase mammalian Ste20-like kinase 1 (MST1) that prevents hyperactivation of the NLRP3 inflammasome. Mechanistically, NLRP3 inflammasome activation induces caspase-1-dependent cleavage of MST1 on its inhibitory linker region, resulting in enhanced kinase activity. The enhanced MST1 phosphorylates the inflammasome adaptor protein ASC at serine 58, disrupting ASC oligomerization and thereby attenuating inflammasome assembly. Notably, staurosporine (STS), a chemical inducer of MST1 cleavage, mitigates inflammation and tissue damage in a lipopolysaccharide (LPS)-induced sepsis mouse model. These findings reveal a negative feedback mechanism for maintaining inflammatory homeostasis and highlight MST1 cleavage as a potential therapeutic target for controlling inflammation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116076"},"PeriodicalIF":6.9,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728314","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
An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease. 一项最新的氧化磷酸化必需基因清单确定了家族性mims病的线粒体起源。
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-07-25 DOI: 10.1016/j.celrep.2025.116069
Marcell Harhai, Mads M Foged, Christine Zarges, Juan C Landoni, Sylvain Chollet, Michele Simonelli, Emeline Recazens, Miriam Lisci, Nora Laban, Suliana Manley, Jan Riemer, Jose Antonio Lopez-Escamez, Anna Lysakowski, Alexis A Jourdain
{"title":"An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.","authors":"Marcell Harhai, Mads M Foged, Christine Zarges, Juan C Landoni, Sylvain Chollet, Michele Simonelli, Emeline Recazens, Miriam Lisci, Nora Laban, Suliana Manley, Jan Riemer, Jose Antonio Lopez-Escamez, Anna Lysakowski, Alexis A Jourdain","doi":"10.1016/j.celrep.2025.116069","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116069","url":null,"abstract":"<p><p>Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism, and dysfunction in oxidative phosphorylation (OXPHOS) is a hallmark. Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging, and, to date, most lack a cure. Here, we build on previous efforts to identify genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 \"growth\" screen, presenting an updated inventory of 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Ménière's disease, and demonstrate that it supports intermembrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in familial Ménière's disease, provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in MDs, with the potential to guide future diagnostics and treatments for MDs.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116069"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717638","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
SUGP1 loss drives SF3B1 hotspot mutant missplicing in cancer. SUGP1缺失驱动SF3B1热点突变在癌症中的错误剪接。
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-07-25 DOI: 10.1016/j.celrep.2025.116075
Peiqi Xing, Pedro Bak-Gordon, Jindou Xie, Jian Zhang, Zhaoqi Liu, James L Manley
{"title":"SUGP1 loss drives SF3B1 hotspot mutant missplicing in cancer.","authors":"Peiqi Xing, Pedro Bak-Gordon, Jindou Xie, Jian Zhang, Zhaoqi Liu, James L Manley","doi":"10.1016/j.celrep.2025.116075","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116075","url":null,"abstract":"<p><p>SF3B1 is the most frequently mutated splicing factor in cancer. Such mutations cause missplicing by promoting aberrant 3' splice site usage; however, how this occurs mechanistically remains controversial. To address this issue, we employed a computational screen of 600 splicing-related proteins to identify those whose reduced expression recapitulates mutant SF3B1-induced splicing dysregulation. Strikingly, our analysis reveals only two proteins whose knockdown or knockout reproduces this effect. Extending our previous findings, loss of the G-patch protein SUGP1 recapitulates almost all splicing defects induced by SF3B1 hotspot mutations. Unexpectedly, loss of the RNA helicase Aquarius (AQR) reproduces ∼40% of these defects. However, we find that AQR knockdown causes significant SUGP1 missplicing and reduced SUGP1 levels, suggesting that AQR loss reproduces mutant SF3B1 splicing defects only indirectly. This study advances our understanding of missplicing caused by oncogenic SF3B1 mutations and highlights the fundamental role of SUGP1 in this process.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116075"},"PeriodicalIF":7.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717642","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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