Molecular Cell最新文献_第2页

Beyond prediction: The evolving role of artificial intelligence in genome editing 超越预测：人工智能在基因组编辑中的演变作用

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-15 DOI: 10.1016/j.molcel.2026.08.025

Soochul Shin,Heesoo Uhm,Yong-Woo Kim,Hyeon Woo Im,Sangsu Bae

引用次数: 0

AI empowers scalable and programmable RNA design 人工智能支持可扩展和可编程的RNA设计

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-15 DOI: 10.1016/j.molcel.2026.09.025

Ziqian Lin,Han Huang,Jiuming Wang,Liang Hong,Irwin King,Yu Li

引用次数: 0

The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology OTULIN的结合抑制LUBAC活性以防止tnf驱动的免疫病理

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-15 DOI: 10.1016/j.molcel.2026.09.039

Wenxin Lyu,Berthe Katrine Fiil,John Rizk,Majken Kjær,Max Benjamin Sauerland,Saulė Špokaitė,Biao Ma,Malin Jessen,Hanna Kulvicki,Rune Busk Damgaard,Paul R. Elliott,Mads Gyrd-Hansen

{"title":"The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology","authors":"Wenxin Lyu,Berthe Katrine Fiil,John Rizk,Majken Kjær,Max Benjamin Sauerland,Saulė Špokaitė,Biao Ma,Malin Jessen,Hanna Kulvicki,Rune Busk Damgaard,Paul R. Elliott,Mads Gyrd-Hansen","doi":"10.1016/j.molcel.2026.09.039","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.039","url":null,"abstract":"Met1-linked ubiquitin chains (Met1-Ub), synthesized by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, regulate inflammatory signaling and cell death. OTULIN activity prevents tumor necrosis factor (TNF)-driven autoinflammatory pathology and embryonic lethality, but the role of the direct OTULIN-LUBAC interaction remains unclear. Here, we show that mice harboring a point mutation in the OTULIN peptide:N-glycanase/UBA- or UBX-containing proteins (PUB)-interacting motif (OTULINY56A), which disrupts LUBAC binding, are viable without spontaneous pathology but are highly sensitive to TNF-induced toxicity and TNF-mediated immunopathology during Listeria monocytogenes infection. Mechanistically, the OTULIN-LUBAC interaction prevents Met1-linked autoubiquitination, thereby limiting LUBAC activity and Met1-Ub conjugation on non-LUBAC substrates. Disrupting the OTULIN-LUBAC interaction increased Met1-Ub accumulation at the TNF receptor signaling complex, which stabilized the signaling complex, increased nuclear factor-kappa B (NF-κB) signaling, and, unlike loss of OTULIN or its activity, protected from TNF-induced apoptosis. Collectively, we identify the OTULIN-LUBAC interaction as a critical brake restricting LUBAC function and Met1-Ub-dependent signaling.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"7 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173058","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

Integration by parts: The multi-layered mechanisms of cis-regulatory control 部分整合：顺式监管的多层次机制

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-15 DOI: 10.1016/j.molcel.2026.09.016

Jake Cornwall-Scoones,James Briscoe,M. Joaquina Delás

{"title":"Integration by parts: The multi-layered mechanisms of cis-regulatory control","authors":"Jake Cornwall-Scoones,James Briscoe,M. Joaquina Delás","doi":"10.1016/j.molcel.2026.09.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.016","url":null,"abstract":"Cis-regulatory elements (CREs) integrate signals from transcription factors (TFs) to control gene expression, yet mechanisms underlying this information processing remain poorly understood. Deep learning demonstrates expression is predictable from CRE sequence, suggesting that unifying principles of regulation are within reach. Here, we propose a framework dividing CRE regulatory logic into two layers: binding-level integration, where cooperative TF interactions modulate DNA occupancy; and transcriptional-level integration, where TF effector domains and cofactors convert binding configurations into expression. At the binding level, we classify TF cooperativity along orthogonal axes—specific versus general, and symmetric versus asymmetric—encompassing protein-protein interactions, nucleosome competition, pioneer activity, and assisted loading. At the transcriptional level, cofactor interactions generate additive, synergistic, or antagonistic logic. Emerging from this complexity is a recurring quantitative pattern: “multiplication plus saturation,” reconciling binding specificity with flexibility, explaining how short DNA motifs generate precise expression while maintaining evolvability, and informing synthetic biology and therapeutic applications.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"24 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173059","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 promise and perils of artificial intelligence in molecular biology 人工智能在分子生物学中的前景和危险

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-15 DOI: 10.1016/j.molcel.2026.09.003

Ellen Zhong,Emmanuel D. Levy,Jianyi Yang,Quan Chen,Alan S.L. Wong,Judith B. Zaugg

引用次数: 0

Inherent electrochemical activity of extrachromosomal DNA hub shapes spatial redox environment in nucleus 染色体外DNA中心固有的电化学活性形成了细胞核内的空间氧化还原环境

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-15 DOI: 10.1016/j.molcel.2026.09.018

Luning Qin,Ting Wu,Shuai Qiao,Shaoting Zheng,Jieshi Zhou,Bijia Cui,Xueting Zhen,Michael W. Chen,Yifan Dai,Heng Zhang,Tao Sun

{"title":"Inherent electrochemical activity of extrachromosomal DNA hub shapes spatial redox environment in nucleus","authors":"Luning Qin,Ting Wu,Shuai Qiao,Shaoting Zheng,Jieshi Zhou,Bijia Cui,Xueting Zhen,Michael W. Chen,Yifan Dai,Heng Zhang,Tao Sun","doi":"10.1016/j.molcel.2026.09.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.018","url":null,"abstract":"Extrachromosomal DNA (ecDNA) is a key element driving the malignant progression of tumors. Since ecDNA lacks canonical high-order chromatin compaction, how it maintains structural and functional stability in highly oxidizing tumor environments remains unclear. Using metabolomics, biochemistry, and imaging assays in human cancer cells and mouse models, we herein show that ecDNA hub establishes an active electrochemical environment, which drives the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) through a non-enzymatic mechanism. GSH forms a protective “cloud” around ecDNA hubs, shielding ecDNA from damage and sustaining oncogene expression. Lastly, using spermidine, which disrupts the interfacial environment of ecDNA hubs, we found that affecting the redox balance of ecDNA hubs drives tumor death. This study uncovers a non-enzymatic function of ecDNA hubs that establishes a self-reinforcing maintenance loop to regulate spatial redox environments, revealing an electrochemical environment-dependent redox-regulation strategy in cancer biology.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"19 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173055","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

Molecular mechanism of residue-specific nucleosome acetylation 残基特异性核小体乙酰化的分子机制

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-15 DOI: 10.1016/j.molcel.2026.09.019

Marisa Müller,Olga Kolesnikova,Matteo Doudin,Andreas W. Thomae,Aline Campos Sparr,Silke Krause,Thomas Hoffmann,Peter B. Becker,Sebastian Eustermann

{"title":"Molecular mechanism of residue-specific nucleosome acetylation","authors":"Marisa Müller,Olga Kolesnikova,Matteo Doudin,Andreas W. Thomae,Aline Campos Sparr,Silke Krause,Thomas Hoffmann,Peter B. Becker,Sebastian Eustermann","doi":"10.1016/j.molcel.2026.09.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.019","url":null,"abstract":"The male-specific lethal (MSL) complex catalyzes global acetylation of histone H4 at lysine 16, a paradigm for understanding how histone acetylation is linked to transcription and disease. However, the dynamic yet specific mechanisms governing the function of MSL histone acetyltransferase (HAT) and other HAT complexes remain largely elusive. Here, we report cryogenic-electron microscopy (cryo-EM) structures of the Drosophila MSL complex engaged during active catalysis, revealing how nucleosomes are acetylated in a residue-specific manner. Unlike typical enzyme-substrate complexes, a stable product state is observed, directly visualizing the acetyl group being transferred from coenzyme A to H4K16. The cooperative interplay of MSL subunits acts as a molecular ruler conferring specificity, while recognition of H3K36 trimethylation accelerates enzymatic activity, linking MSL function to transcriptionally active gene bodies. We establish physiological relevance of this mechanism in Drosophila dosage compensation. These findings uncover molecular principles underlying the specificity and regulation of histone acetylation in transcriptionally active chromatin.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"53 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173056","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

STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury 在肺缺血再灌注损伤中，STING参与PKR驱动溶酶体细胞死亡

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-14 DOI: 10.1016/j.molcel.2026.09.024

Peigen Gao,Tao Wang,Yingjian Liu,Fenghui Zhuang,Chongwu Li,Guodong Wu,Yifang Dang,Huikang Xie,Chenyang Dai,Mengmeng Zhao,Deping Zhao,Xiangyang Wu,Chang Chen,Haipeng Liu,Junqi Wu

{"title":"STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury","authors":"Peigen Gao,Tao Wang,Yingjian Liu,Fenghui Zhuang,Chongwu Li,Guodong Wu,Yifang Dang,Huikang Xie,Chenyang Dai,Mengmeng Zhao,Deping Zhao,Xiangyang Wu,Chang Chen,Haipeng Liu,Junqi Wu","doi":"10.1016/j.molcel.2026.09.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.024","url":null,"abstract":"Stimulator of interferon genes (STING) has been implicated in multiple forms of cell death. However, the effector kinases that couple STING to these death programs remain poorly defined. Here, we show that during lung ischemia-reperfusion injury, mitochondrial DNA release engages the cyclic GMP-AMP synthase (cGAS)-STING pathway to trigger lysosomal cell death (LCD) in mouse and rat models. In human lung epithelial cells, STING oligomerization at the endoplasmic reticulum drives autophosphorylation of double-stranded RNA-dependent protein kinase (PKR) at serine 33. This phosphorylation of PKR activates IκB kinase-NF-κB signaling independently of the canonical STING-TBK1 and PKR-eIF2α pathways. In turn, NF-κB induces LAMP3 transcription, promoting lysosomal membrane permeabilization and LCD. STING-PKR signaling is also observed in patient-derived lung epithelial cells and alveolar organoids. These findings identify PKR as a non-canonical STING effector and show that blockade of STING-PKR signaling attenuates epithelial LCD and lung injury.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"11 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172373","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

Structural basis of directionality control in large serine integrases 大型丝氨酸整合酶方向性控制的结构基础

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-13 DOI: 10.1016/j.molcel.2026.09.028

Heewhan Shin,Ying Pigli,Tania Peña Reyes,Adebayo J. Bello,Oluwateniola T. Taiwo-Aiyerin,James R. Fuller,Femi J. Olorunniji,Phoebe A. Rice

{"title":"Structural basis of directionality control in large serine integrases","authors":"Heewhan Shin,Ying Pigli,Tania Peña Reyes,Adebayo J. Bello,Oluwateniola T. Taiwo-Aiyerin,James R. Fuller,Femi J. Olorunniji,Phoebe A. Rice","doi":"10.1016/j.molcel.2026.09.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.028","url":null,"abstract":"Large serine integrases catalyze unidirectional insertion of large DNA payloads and, in the presence of a cognate recombination directionality factor (RDF), catalyze unidirectional excision. Understanding how directionality is enforced has been hampered by a lack of structural information. Here, we report 8 structures of SPβ integrase-DNA complexes along the integrative (−RDF) and excisive (+RDF) reaction pathways at resolutions extending to 3.15 Å. These include tetrameric intermediates before and after strand exchange and product-bound dimers for both pathways. We find that recombination-induced conformational changes and RDF-mediated repositioning of the integrase’s coiled-coil subdomain (1) dictate which pairs of DNA sites can be assembled into active synaptic complexes and (2) dictate which product complexes will be conformationally locked, preventing back reactions. Critically, we find that the synaptic complex in which excision occurs is fundamentally different from that in which integration occurs. These insights provide a framework for engineering improved genome editing tools.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"11 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152665","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

Reverse transcribed ssDNA derepresses translation of a retron antiviral protein 逆转录的ssDNA抑制逆转录抗病毒蛋白的翻译

IF 16 1区生物学

Molecular Cell Pub Date : 2026-10-13 DOI: 10.1016/j.molcel.2026.09.026

Karen Zhang,Matías Rojas-Montero,Darshini Poola,Josepha M. Klas,Arturo Carabias,Dennis J. Zhang,Mario R. Mestre,Ruiliang Zhao,Ana Dávila-Hidalgo,Lieza Chan,Kliment A. Verba,Guillermo Montoya,Rafael Pinilla-Redondo,Alejandro González-Delgado,Seth L. Shipman

{"title":"Reverse transcribed ssDNA derepresses translation of a retron antiviral protein","authors":"Karen Zhang,Matías Rojas-Montero,Darshini Poola,Josepha M. Klas,Arturo Carabias,Dennis J. Zhang,Mario R. Mestre,Ruiliang Zhao,Ana Dávila-Hidalgo,Lieza Chan,Kliment A. Verba,Guillermo Montoya,Rafael Pinilla-Redondo,Alejandro González-Delgado,Seth L. Shipman","doi":"10.1016/j.molcel.2026.09.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.09.026","url":null,"abstract":"Retrons are bacterial immune systems that prevent phage propagation by initiating a toxic response within infected hosts. Previously characterized retrons produce abundant multicopy single-stranded DNA (msDNA) by reverse transcription, which acts as an antitoxin in the absence of phage. However, we describe here a non-canonical mechanism for type VI retrons, which do not produce detectable msDNA in the absence of phage yet still provide defense. Focusing on Retron-Vpa2 from V. parahaemolyticus, we show broad defense against phages and identify triggers of the system when expressed in E. coli. Within the retron operon, we find a highly enriched, structured transcript that we term a hybrid RNA (hyRNA). The hyRNA contains the reverse transcription template and a toxin coding sequence that is repressed by a riboregulator. In our model of triggering, phage infection induces accumulation of msDNA, which hybridizes to the riboregulator and enables RNase H cleavage, derepressing translation of the toxin.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"3 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152667","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