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Tracing the evolutionary history of the CCR5delta32 deletion via ancient and modern genomes 通过古今基因组追踪CCR5delta32缺失的进化史
IF 64.5 1区 生物学
Cell Pub Date : 2025-05-05 DOI: 10.1016/j.cell.2025.04.015
Kirstine Ravn, Leonardo Cobuccio, Rasa Audange Muktupavela, Jonas Meisner, Lasse Schnell Danielsen, Michael Eriksen Benros, Thorfinn Sand Korneliussen, Martin Sikora, Eske Willerslev, Morten E. Allentoft, Evan K. Irving-Pease, Simon Rasmussen
{"title":"Tracing the evolutionary history of the CCR5delta32 deletion via ancient and modern genomes","authors":"Kirstine Ravn, Leonardo Cobuccio, Rasa Audange Muktupavela, Jonas Meisner, Lasse Schnell Danielsen, Michael Eriksen Benros, Thorfinn Sand Korneliussen, Martin Sikora, Eske Willerslev, Morten E. Allentoft, Evan K. Irving-Pease, Simon Rasmussen","doi":"10.1016/j.cell.2025.04.015","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.015","url":null,"abstract":"The chemokine receptor variant CCR5delta32 is linked to HIV-1 resistance and other conditions. Its evolutionary history and allele frequency (10%–16%) in European populations have been extensively debated. We provide a detailed perspective of the evolutionary history of the deletion through time and space. We discovered that the CCR5delta32 allele arose on a pre-existing haplotype consisting of 84 variants. Using this information, we developed a haplotype-aware probabilistic model to screen 934 low-coverage ancient genomes and traced the origin of the CCR5delta32 deletion to at least 6,700 years before the present (BP) in the Western Eurasian Steppe region. Furthermore, we present strong evidence for positive selection acting upon the CCR5delta32 haplotype between 8,000 and 2,000 years BP in Western Eurasia and show that the presence of the haplotype in Latin America can be explained by post-Columbian genetic exchanges. Finally, we point to complex CCR5delta32 genotype-haplotype-phenotype relationships, which demand consideration when targeting the CCR5 receptor for therapeutic strategies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"113 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905439","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
Genomes of critically endangered saola are shaped by population structure and purging 极度濒危的索拉的基因组受到种群结构和净化的影响
IF 64.5 1区 生物学
Cell Pub Date : 2025-05-05 DOI: 10.1016/j.cell.2025.03.040
Genís Garcia-Erill, Shanlin Liu, Minh Duc Le, Martha M. Hurley, Hung Dinh Nguyen, Dzung Quoc Nguyen, Dzung Huy Nguyen, Cindy G. Santander, Fátima Sánchez Barreiro, Nuno Filipe Gomes Martins, Kristian Hanghøj, Faezah Mohd Salleh, Jazmín Ramos-Madrigal, Xi Wang, Mikkel-Holger S. Sinding, Hernán E. Morales, Frederik Filip Stæger, Nicholas Wilkinson, Guanliang Meng, Patrícia Pečnerová, Rasmus Heller
{"title":"Genomes of critically endangered saola are shaped by population structure and purging","authors":"Genís Garcia-Erill, Shanlin Liu, Minh Duc Le, Martha M. Hurley, Hung Dinh Nguyen, Dzung Quoc Nguyen, Dzung Huy Nguyen, Cindy G. Santander, Fátima Sánchez Barreiro, Nuno Filipe Gomes Martins, Kristian Hanghøj, Faezah Mohd Salleh, Jazmín Ramos-Madrigal, Xi Wang, Mikkel-Holger S. Sinding, Hernán E. Morales, Frederik Filip Stæger, Nicholas Wilkinson, Guanliang Meng, Patrícia Pečnerová, Rasmus Heller","doi":"10.1016/j.cell.2025.03.040","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.040","url":null,"abstract":"The saola is one of the most elusive large mammals, standing at the brink of extinction. We constructed a reference genome and resequenced 26 saola individuals, confirming the saola as a basal member of the Bovini. Despite its small geographic range, we found that the saola is partitioned into two populations with high genetic differentiation (<em>F</em><sub>ST</sub> = 0.49). We estimate that these populations diverged and started declining 5,000–20,000 years ago, possibly due to climate changes and exacerbated by increasing human activities. The saola has long tracts without genomic diversity; however, most of these tracts are not shared by the two populations. Saolas carry a high genetic load, yet their gradual decline resulted in the purging of the most deleterious genetic variation. Finally, we find that combining the two populations, e.g., in an eventual captive breeding program, would mitigate the genetic load and increase the odds of species survival.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905438","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
Snake venom protection by a cocktail of varespladib and broadly neutralizing human antibodies 由varespladib和广泛中和的人类抗体混合而成的蛇毒保护
IF 64.5 1区 生物学
Cell Pub Date : 2025-05-02 DOI: 10.1016/j.cell.2025.03.050
Jacob Glanville, Mark Bellin, Sergei Pletnev, Baoshan Zhang, Joel Christian Andrade, Sangil Kim, David Tsao, Raffaello Verardi, Rishi Bedi, Sindy Liao, Raymond Newland, Nicholas L. Bayless, Sawsan Youssef, Ena S. Tully, Tatsiana Bylund, Sujeong Kim, Hannah Hirou, Tracy Liu, Peter D. Kwong
{"title":"Snake venom protection by a cocktail of varespladib and broadly neutralizing human antibodies","authors":"Jacob Glanville, Mark Bellin, Sergei Pletnev, Baoshan Zhang, Joel Christian Andrade, Sangil Kim, David Tsao, Raffaello Verardi, Rishi Bedi, Sindy Liao, Raymond Newland, Nicholas L. Bayless, Sawsan Youssef, Ena S. Tully, Tatsiana Bylund, Sujeong Kim, Hannah Hirou, Tracy Liu, Peter D. Kwong","doi":"10.1016/j.cell.2025.03.050","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.050","url":null,"abstract":"Snake envenomation is a neglected tropical disease, with 600 species causing over 100,000 deaths and 300,000 permanent disabilities in humans annually. Broadly neutralizing antibodies and broad chemical inhibitors have been proposed as solutions, but how to develop a therapeutically effective cocktail and the number of required components have been unclear. To address this gap, we iteratively recovered two broadly neutralizing antivenom antibodies from the memory B cells of a hyperimmune human donor with extensive snake venom exposure. The antibodies recognized conserved neutralizing epitopes on prevalent long and short snake neurotoxins, with crystal structures revealing antibody mimicry of the interfaces between these neurotoxins and their host target, the nicotinic acetylcholine receptor. We combined and tested these antibodies and the phospholipase inhibitor varespladib. A 3-component cocktail rescued animals from whole-venom challenge of all species in a 19-member WHO Category 1 and Category 2 elapid diversity set, with complete protection against most snakes observed.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"48 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897888","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
Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory 长期组蛋白乳酸化与先天免疫记忆中的代谢和表观遗传重新布线有关
IF 64.5 1区 生物学
Cell Pub Date : 2025-05-02 DOI: 10.1016/j.cell.2025.03.048
Athanasios Ziogas, Boris Novakovic, Lorenzo Ventriglia, Noriko Galang, Kim A. Tran, Wenchao Li, Vasiliki Matzaraki, Nienke van Unen, Titus Schlüter, Anaísa V. Ferreira, Simone J.C.F.M. Moorlag, Valerie A.C.M. Koeken, Mthabisi Moyo, Xiaolin Li, Marijke P.A. Baltissen, Joost H.A. Martens, Yang Li, Maziar Divangahi, Leo A.B. Joosten, Musa M. Mhlanga, Mihai G. Netea
{"title":"Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory","authors":"Athanasios Ziogas, Boris Novakovic, Lorenzo Ventriglia, Noriko Galang, Kim A. Tran, Wenchao Li, Vasiliki Matzaraki, Nienke van Unen, Titus Schlüter, Anaísa V. Ferreira, Simone J.C.F.M. Moorlag, Valerie A.C.M. Koeken, Mthabisi Moyo, Xiaolin Li, Marijke P.A. Baltissen, Joost H.A. Martens, Yang Li, Maziar Divangahi, Leo A.B. Joosten, Musa M. Mhlanga, Mihai G. Netea","doi":"10.1016/j.cell.2025.03.048","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.048","url":null,"abstract":"Trained immunity, a <em>de facto</em> innate immune memory characterized by enhanced responsiveness to future challenges, is underpinned by epigenetic and metabolic rewiring. In individuals vaccinated with Bacille Calmette-Guérin (BCG), lactate release was associated with enhanced cytokine responsiveness upon restimulation. Trained monocytes/macrophages are characterized by lactylation of histone H3 at lysine residue 18(H3K18la), mainly at distal regulatory regions. Histone lactylation was positively associated with active chromatin and gene transcription, persisted after the elimination of the training stimulus, and was strongly associated with “trained” gene transcription in response to a secondary stimulus. Increased lactate production upon induction of trained immunity led to enhanced production of proinflammatory cytokines, a process associated with histone lactylation. Pharmacological inhibition of lactate production or histone lactylation blocked trained immunity responses, while polymorphisms of <em>LDHA</em> and <em>EP300</em> genes modulated trained immunity. Long-term histone lactylation persisted <em>in vivo</em> 90 days after vaccination with BCG, highlighting H3K18la as an epigenetic mark of innate immune memory.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"111 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897887","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
Unlocking LAG3: Ubiquitin’s unexpected role 解锁LAG3:泛素的意外作用
IF 64.5 1区 生物学
Cell Pub Date : 2025-05-01 DOI: 10.1016/j.cell.2025.03.030
Ye Zhao, Kai W. Wucherpfennig
{"title":"Unlocking LAG3: Ubiquitin’s unexpected role","authors":"Ye Zhao, Kai W. Wucherpfennig","doi":"10.1016/j.cell.2025.03.030","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.030","url":null,"abstract":"The inhibitory receptor LAG3 is the target of the FDA-approved mAb relatlimab, but its mechanism of signaling is not well understood. In this issue of <em>Cell</em>, Jiang et al. demonstrate that ubiquitination of its cytoplasmic domain is essential for the inhibitory function of LAG3. Co-expression of LAG3 and the CBL E3 ligases represents a biomarker of clinical response to LAG3 inhibition in human melanoma.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893229","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
Mutant macrophages CHIP in to help solid tumors 巨噬细胞突变帮助实体肿瘤
IF 64.5 1区 生物学
Cell Pub Date : 2025-05-01 DOI: 10.1016/j.cell.2025.03.049
Isak W. Tengesdal, Siddhartha Jaiswal
{"title":"Mutant macrophages CHIP in to help solid tumors","authors":"Isak W. Tengesdal, Siddhartha Jaiswal","doi":"10.1016/j.cell.2025.03.049","DOIUrl":"https://doi.org/10.1016/j.cell.2025.03.049","url":null,"abstract":"Clonal hematopoiesis of indeterminate potential (CHIP) promotes adverse outcomes in age-related diseases. However, the impact of CHIP on solid tumors has yet to be elucidated in large-scale cancer-focused cohorts. In a recently published article in the <em>New England Journal of Medicine</em>, Pich et al. provide evidence for a tumor-promoting role of CHIP in solid malignancies.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"20 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893230","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 natural gene on-off system confers field thermotolerance for grain quality and yield in rice 一个天然的基因开关系统赋予水稻的籽粒品质和产量的田间耐热性
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-30 DOI: 10.1016/j.cell.2025.04.011
Wei Li, Ke Yang, Chaofan Hu, Waseem Abbas, Jian Zhang, Pengkun Xu, Bo Cheng, Juncheng Zhang, Wenjing Yin, Abdullah Shalmani, Lianghuan Qu, Qingya Lv, Bingchen Li, Yuqing He, Xuelei Lai, Lizhong Xiong, Qifa Zhang, Yibo Li
{"title":"A natural gene on-off system confers field thermotolerance for grain quality and yield in rice","authors":"Wei Li, Ke Yang, Chaofan Hu, Waseem Abbas, Jian Zhang, Pengkun Xu, Bo Cheng, Juncheng Zhang, Wenjing Yin, Abdullah Shalmani, Lianghuan Qu, Qingya Lv, Bingchen Li, Yuqing He, Xuelei Lai, Lizhong Xiong, Qifa Zhang, Yibo Li","doi":"10.1016/j.cell.2025.04.011","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.011","url":null,"abstract":"Rising global temperatures threaten crop grain quality and yield; however, how temperature regulates grain quality and how to achieve synergistic thermotolerance for both quality and yield remain unknown. Here, we identified a rice major locus, <em>QT12</em>, which negatively controls grain-quality field thermotolerance by disrupting endosperm storage substance homeostasis through over-activating unfolded protein response (UPR). Natural variations in <em>QT12</em> and an NF-Y complex form a natural gene on-off system to modulate <em>QT12</em> expression and thermotolerance. High temperatures weaken NF-YB9/NF-YC10 interactions with NF-YA8, releasing <em>QT12</em> suppression and triggering quality deterioration. Low <em>QT12</em> expression confers superior quality and increases elite rice yield up to 1.31–1.93 times under large-scale high-temperature trials. Two trait regulatory haplotypes (TRHs) from co-selected variations of the four genetically unlinked genes in NF-Ys-<em>QT12</em> were identified for subspecies thermotolerance differentiation. Our work provides mechanistic insights into rice field thermotolerance and offers a proof-of-concept breeding strategy to break stress-growth and yield-quality trade-offs.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"35 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889897","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
Global genetic structure of human gut microbiome species is related to geographic location and host health 人类肠道微生物群物种的整体遗传结构与地理位置和宿主健康有关
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-30 DOI: 10.1016/j.cell.2025.04.014
Sergio Andreu-Sánchez, Aitor Blanco-Míguez, Daoming Wang, Davide Golzato, Paolo Manghi, Vitor Heidrich, Gloria Fackelmann, Daria V. Zhernakova, Alexander Kurilshikov, Mireia Valles-Colomer, Rinse K. Weersma, Alexandra Zhernakova, Jingyuan Fu, Nicola Segata
{"title":"Global genetic structure of human gut microbiome species is related to geographic location and host health","authors":"Sergio Andreu-Sánchez, Aitor Blanco-Míguez, Daoming Wang, Davide Golzato, Paolo Manghi, Vitor Heidrich, Gloria Fackelmann, Daria V. Zhernakova, Alexander Kurilshikov, Mireia Valles-Colomer, Rinse K. Weersma, Alexandra Zhernakova, Jingyuan Fu, Nicola Segata","doi":"10.1016/j.cell.2025.04.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.014","url":null,"abstract":"The human gut harbors thousands of microbial species, each exhibiting significant inter-individual genetic variability. Although many studies have associated microbial relative abundances with human-health-related phenotypes, the substantial intraspecies genetic variability of gut microbes has not yet been comprehensively considered, limiting the potential of linking such genetic traits with host conditions. Here, we analyzed 32,152 metagenomes from 94 microbiome studies across the globe to investigate the human microbiome intraspecies genetic diversity. We reconstructed 583 species-specific phylogenies and linked them to geographic information and species’ horizontal transmissibility. We identified 484 microbial-strain-level associations with 241 host phenotypes, encompassing human anthropometric factors, biochemical measurements, diseases, and lifestyle. We observed a higher prevalence of a <em>Ruminococcus gnavus</em> clade in nonagenarians correlated with distinct plasma bile acid profiles and a melanoma and prostate-cancer-associated <em>Collinsella</em> clade. Our large-scale intraspecies genetic analysis highlights the relevance of strain diversity as it relates to human health.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"15 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889898","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
Neural-activity-regulated and glia-mediated control of brain lymphatic development 脑淋巴发育的神经活动调节和神经胶质介导控制
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-30 DOI: 10.1016/j.cell.2025.04.008
Jia Li, Ming-Jian Liu, Wen-Jie Du, Xiao-Lan Peng, Hao Deng, Hua-Xing Zi, Han-Bing Shang, Jiu-Lin Du
{"title":"Neural-activity-regulated and glia-mediated control of brain lymphatic development","authors":"Jia Li, Ming-Jian Liu, Wen-Jie Du, Xiao-Lan Peng, Hao Deng, Hua-Xing Zi, Han-Bing Shang, Jiu-Lin Du","doi":"10.1016/j.cell.2025.04.008","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.008","url":null,"abstract":"The nervous system regulates peripheral immune responses under physiological and pathological conditions, but the brain’s impact on immune system development remains unknown. Meningeal mural lymphatic endothelial cells (muLECs), embedded in the leptomeninges, form an immune niche surrounding the brain that contributes to brain immunosurveillance. Here, we report that the brain controls the development of muLECs via a specialized glial subpopulation, <em>slc6a11b+</em> radial astrocytes (RAs), a process modulated by neural activity in zebrafish. <em>slc6a11b+</em> RAs, with processes extending to the meninges, govern muLEC formation by expressing vascular endothelial growth factor C (<em>vegfc</em>). Moreover, neural activity regulates muLEC development, and this regulation requires Vegfc in <em>slc6a11b+</em> RAs. Intriguingly, <em>slc6a11b+</em> RAs cooperate with calcium-binding EGF domain 1 (<em>ccbe1</em>)+ fibroblasts to restrict muLEC growth on the brain surface via controlling mature Vegfc distribution. Thus, our study uncovers a glia-mediated and neural-activity-regulated control of brain lymphatic development and highlights the importance of inter-tissue cellular cooperation in development.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"104 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890277","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
tRNA modifications tune m6A-dependent mRNA decay tRNA修饰调整依赖m6a的mRNA衰变
IF 64.5 1区 生物学
Cell Pub Date : 2025-04-30 DOI: 10.1016/j.cell.2025.04.013
Bastian Linder, Puneet Sharma, Jie Wu, Tosca Birbaumer, Cristian Eggers, Shino Murakami, Roman E. Ott, Kai Fenzl, Hannah Vorgerd, Florian Erhard, Samie R. Jaffrey, Sebastian A. Leidel, Lars M. Steinmetz
{"title":"tRNA modifications tune m6A-dependent mRNA decay","authors":"Bastian Linder, Puneet Sharma, Jie Wu, Tosca Birbaumer, Cristian Eggers, Shino Murakami, Roman E. Ott, Kai Fenzl, Hannah Vorgerd, Florian Erhard, Samie R. Jaffrey, Sebastian A. Leidel, Lars M. Steinmetz","doi":"10.1016/j.cell.2025.04.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.04.013","url":null,"abstract":"Chemically modified nucleotides in mRNA are critical regulators of gene expression, primarily through interactions with reader proteins that bind to these modifications. Here, we present a mechanism by which the epitranscriptomic mark <em>N</em><sup>6</sup>-methyladenosine (m<sup>6</sup>A) is read by tRNAs during translation. Codons that are modified with m<sup>6</sup>A are decoded inefficiently by the ribosome, rendering them “non-optimal” and inducing ribosome collisions on cellular transcripts. This couples mRNA translation to decay. 5-Methoxycarbonylmethyl-2-thiouridine (mcm<sup>5</sup>s<sup>2</sup>U) in the tRNA anticodon loop counteracts this effect. This unanticipated link between the mRNA and tRNA epitranscriptomes enables the coordinated decay of mRNA regulons, including those encoding oncogenic signaling pathways. In cancer, dysregulation of the m<sup>6</sup>A and mcm<sup>5</sup>s<sup>2</sup>U biogenesis pathways—marked by a shift toward more mcm<sup>5</sup>s<sup>2</sup>U—is associated with more aggressive tumors and poor prognosis. Overall, this pan-epitranscriptomic interaction represents a novel mechanism of post-transcriptional gene regulation with implications for human health.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11632 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890262","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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