Molecular Cell最新文献_第9页

A protein-dependent riboswitch activates ribosomal frameshifting in cardioviruses 一种蛋白质依赖的核糖体开关激活心脏病毒的核糖体移框

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-21 DOI: 10.1016/j.molcel.2026.07.036

Jemma K. Betts,Cy M. Jeffries,Tim C. Passchier,Hermia C.Y. Kung,Sarah P. Graham,Mahmoud A.S. Abdelhamid,Jamieson A.L. Howard,Timothy D. Craggs,Stephen C. Graham,Ian Brierley,Mark C. Leake,Steven D. Quinn,Chris H. Hill

{"title":"A protein-dependent riboswitch activates ribosomal frameshifting in cardioviruses","authors":"Jemma K. Betts,Cy M. Jeffries,Tim C. Passchier,Hermia C.Y. Kung,Sarah P. Graham,Mahmoud A.S. Abdelhamid,Jamieson A.L. Howard,Timothy D. Craggs,Stephen C. Graham,Ian Brierley,Mark C. Leake,Steven D. Quinn,Chris H. Hill","doi":"10.1016/j.molcel.2026.07.036","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.07.036","url":null,"abstract":"Programmed −1 ribosomal frameshifting (PRF) is a translational control mechanism used by RNA viruses to regulate the relative abundance of proteins encoded in different reading frames. Cardioviruses exhibit the highest known PRF efficiency, with ∼85% of ribosomes shifting into the −1 frame. This unusual event requires an interaction between the viral 2A protein and a stimulatory element in the RNA genome, but the basis for protein dependence is unclear. To address this, here we investigate the structure and dynamics of the PRF signal in Theiler’s murine encephalitis virus (TMEV). By combining X-ray crystallography, small-angle X-ray scattering (SAXS), and single-molecule fluorescence resonance energy transfer (smFRET), we show that 2A binding switches the RNA from a stem-loop conformation into a pseudoknot, and we demonstrate that pseudoknot formation is essential for efficient PRF in vitro and in cells. Together, these findings illustrate how the cardiovirus PRF element behaves as a protein-dependent riboswitch, defining the molecular mechanism by which frameshifting is conditionally activated.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"125 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768878","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

Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma 烟酰胺核苷酸转氢酶直接将神经胶质瘤中的氧化还原稳态与脯氨酸生物合成结合起来

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-21 DOI: 10.1016/j.molcel.2026.07.031

Lisa A. Vettore,Adam Boufersaoui,Yingying Lyu,Anaïs Oudin,Keene L. Abbott,Sonu Subudhi,Yetiş Gültekin,Katherine L. Eales,Ishana Rajgopal,Cristina Escribano-Gonzalez,Rahatil A. Chowdhury,Himani Rana,Victoria Wykes,Rakesh K. Jain,Anna Golebiewska,Matthew G. Vander Heiden,Daniel A. Tennant

{"title":"Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma","authors":"Lisa A. Vettore,Adam Boufersaoui,Yingying Lyu,Anaïs Oudin,Keene L. Abbott,Sonu Subudhi,Yetiş Gültekin,Katherine L. Eales,Ishana Rajgopal,Cristina Escribano-Gonzalez,Rahatil A. Chowdhury,Himani Rana,Victoria Wykes,Rakesh K. Jain,Anna Golebiewska,Matthew G. Vander Heiden,Daniel A. Tennant","doi":"10.1016/j.molcel.2026.07.031","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.07.031","url":null,"abstract":"Cancer cell proliferation requires a precise balance between biomass production and nutrient catabolism. The pyridine nucleotide cofactors nicotinamide adenine dinucleotide NAD(H) and NAD phosphate NADP(H) are central to this process, but their compartment-specific regulation is incompletely understood. Using in vivo isotope-labeled metabolite tracing in an orthotopic xenograft model, we find that human gliomas extensively synthesize proline, an amino acid previously associated with hypoxia tolerance. In glioma cells, we identify a hypoxia-enhanced proliferative sensitivity to environmental proline dependent on NADH to NADPH transhydrogenation from a spatially compartmentalized mitochondrial pool by the enzyme nicotinamide nucleotide transhydrogenase (NNT). We demonstrate NNT-dependent generation of mitochondrial NADPH is important for proline accumulation, maintenance of antioxidant systems, and reductive metabolism in hypoxic glioma cells in vitro and tumor progression in vivo. Collectively, these results highlight proline accumulation as a marker of mitochondrial NAD(P)(H) homeostasis and NNT as a specific metabolic dependency in human glioma.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"101 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768914","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 negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand. 线粒体复合体I组装的负调节使呼吸适应细胞能量需求。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-06-26 DOI: 10.1016/j.molcel.2026.06.018

Zhirong Li, Nuo Chen, Caixia Zhou, Lingna Xu, Xiyuan Wang, Hong Xu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong

{"title":"A negative regulator of mitochondrial complex I assembly adapts respiration to cellular energy demand.","authors":"Zhirong Li, Nuo Chen, Caixia Zhou, Lingna Xu, Xiyuan Wang, Hong Xu, Weina Shang, Jun-Ping Liu, Liquan Wang, Chao Tong","doi":"10.1016/j.molcel.2026.06.018","DOIUrl":"10.1016/j.molcel.2026.06.018","url":null,"abstract":"How mitochondrial respiration is tightly regulated by energy demand remains incompletely defined. When mammalian cells switch from glucose to galactose as a carbon source, we observed the enhanced assembly of respiratory chain complexes accompanied by a marked reduction in TMEM141, a mitochondrial inner membrane protein. Loss of TMEM141 increased mitochondrial respiration and promoted complex I assembly, whereas galactose-induced complex I assembly was markedly blunted in TMEM141-deficient cells. TMEM141 interacts with the complex I assembly factor TIMMDC1, limiting its association with complex I subunits. TMEM141 is degraded by the mitochondrial proteases AFG3L2 and YME1L1, and galactose treatment strengthens their interactions. TMEM141 deficiency increases oxidative damage and mtDNA release, leading to activation of the cGAS-STING pathway. In Drosophila, dTMEM141 localizes to mitochondria, modulates mitochondrial activity, and is required for glial cell integrity in the eye. Together, our findings reveal TMEM141 as a negative regulator of complex I assembly that adapts to oxidative phosphorylation (OXPHOS) demands.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3277-3293.e7"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339399","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

Coordination of ALT telomere maintenance across the cell cycle. 细胞周期中ALT端粒维护的协调。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-08-06 DOI: 10.1016/j.molcel.2026.06.037

Julia Vornberger, Matthias Altmeyer

引用次数: 0

BRAF and MEK caught in flagrante delicto BRAF和MEK当场被抓

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 DOI: 10.1016/j.molcel.2026.07.030

Dong Man Jang,Michael J. Eck

引用次数: 0

Biomolecular condensates can function as inherent catalysts. 生物分子凝聚物可以作为内在的催化剂。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-24 DOI: 10.1016/j.molcel.2026.07.008

Michael W Chen, Xiao Guo, Mina Farag, Naixin Qian, Xiaowei Song, Anton Ni, Vicky Liu, Yu Xia, Yuefeng Ma, Leshan Yang, Wen Yu, Matthew R King, Joonho Lee, Richard N Zare, Wei Min, Rohit V Pappu, Yifan Dai

{"title":"Biomolecular condensates can function as inherent catalysts.","authors":"Michael W Chen, Xiao Guo, Mina Farag, Naixin Qian, Xiaowei Song, Anton Ni, Vicky Liu, Yu Xia, Yuefeng Ma, Leshan Yang, Wen Yu, Matthew R King, Joonho Lee, Richard N Zare, Wei Min, Rohit V Pappu, Yifan Dai","doi":"10.1016/j.molcel.2026.07.008","DOIUrl":"10.1016/j.molcel.2026.07.008","url":null,"abstract":"Biomolecular condensates possess distinct solvent environments. This has been postulated to affect biochemical activities. Here, we report the discovery of inherent catalytic functions of condensates formed by intrinsically disordered proteins. The proteins themselves lack any catalytic activities. The catalytic functions of condensates emerge as a consequence of phase separation-dependent mesoscale electrochemical microenvironments. Condensates can mediate the hydrolysis of diverse types of biologically relevant substrates. Through sequence design that enriches selective residues at condensate interfaces, interfacial electrochemical properties, such as interfacial electric field and water activity, are shown to control catalytic behaviors. Synthetic condensates in live cells exhibit hydrolytic activity, reshaping transcription profiles and activating gene circuits that depend on hydrolytic products. Together, these findings support a model that biomolecular condensates function as \"condenzymes,\" contributing emergent biochemical functions in cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3310-3331.e10"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13492180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanism of MEK1 phosphorylation by the N-terminal acidic motif-mediated asymmetric BRAF dimer. n端酸性基序介导的不对称BRAF二聚体介导MEK1磷酸化的机制。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-21 DOI: 10.1016/j.molcel.2026.06.039

Yasushi Kondo, Judith Notbohm, Ignacio Navas Camacho, Gabriela Nagy-Davidescu, Thomas Mason, Jonas Mühle, Jörg Standfuss, Tina Perica

{"title":"Mechanism of MEK1 phosphorylation by the N-terminal acidic motif-mediated asymmetric BRAF dimer.","authors":"Yasushi Kondo, Judith Notbohm, Ignacio Navas Camacho, Gabriela Nagy-Davidescu, Thomas Mason, Jonas Mühle, Jörg Standfuss, Tina Perica","doi":"10.1016/j.molcel.2026.06.039","DOIUrl":"10.1016/j.molcel.2026.06.039","url":null,"abstract":"The rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (RAF/MEK/ERK) signaling cascade regulates cell proliferation and differentiation and is frequently dysregulated in cancer. Approximately 90% of RAF-mutant cancers harbor mutations in B-type rapidly accelerated fibrosarcoma (BRAF). Its proto-oncogenicity is attributed to a four-residue N-terminal acidic (NtA) motif. Although a long-standing model proposes that the NtA promotes activating asymmetric RAF dimerization, the model lacks structural support. Here, we present structures of NtA-mediated asymmetric BRAF dimers bound to their substrate MEK1. Cellular and biochemical data show that the NtA is not required for KRAS-mediated BRAF recruitment to the plasma membrane but is required for the fully catalytically active state. The structure capturing BRAF in a post-catalytic state bound to Ser222-phosphorylated MEK1 further supports this model. The combination of structural and cellular data corroborates the model of NtA-driven asymmetry in BRAF activation and resolves a long-standing disconnect between RAF cancer genetics and structural biology.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3294-3309.e7"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549886","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

Transcriptional kinases drive gene expression network plasticity 转录激酶驱动基因表达网络的可塑性

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 DOI: 10.1016/j.molcel.2026.07.035

David Daesung Lowe,Ali Shilatifard

{"title":"Transcriptional kinases drive gene expression network plasticity","authors":"David Daesung Lowe,Ali Shilatifard","doi":"10.1016/j.molcel.2026.07.035","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.07.035","url":null,"abstract":"Eukaryotic transcription is a highly dynamic and adaptable process that underpins the gene expression programs regulating development, cellular identity, and responses to extracellular signals. Gene-specific regulation of transcription across different cell types and environmental conditions is therefore fundamental to both normal physiology and disease. This specificity is shaped by phosphorylation of the RNA polymerase II (RNAPII) C-terminal domain (CTD) and its associated transcription factors. While cyclin-dependent kinases (CDKs) have long been recognized as the regulators of RNAPII activity, emerging evidence points to a broader, more diverse network of transcriptional kinases. Here, we highlight non-canonical transcriptional kinases that could operate alongside and beyond CDKs to modulate transcription by RNAPII. We discuss how these kinases could introduce context-specific CTD modifications that enable transcriptional plasticity, facilitate rapid loci-specific activation, and integrate signaling and stress-responsive pathways, ultimately adding a layer of regulatory complexity with profound implications for dynamic transcriptional regulation in development, homeostasis, and disease.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"8 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768879","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 art of mimicry: How a plant NLR outwits fungal effectors 模仿的艺术：植物NLR如何战胜真菌效应

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 DOI: 10.1016/j.molcel.2026.07.033

Zian Ye,Yonglin Wu,Xiaoyuan Li,Mingjun Gao,Zuhua He

引用次数: 0

Uridine cytidine kinase 1 promotes phosphatidylcholine biosynthesis, facilitating SARS-CoV-2 infection. 尿苷胞苷激酶1促进磷脂酰胆碱生物合成，促进SARS-CoV-2感染。

IF 16 1区生物学

Molecular Cell Pub Date : 2026-08-20 Epub Date: 2026-07-21 DOI: 10.1016/j.molcel.2026.06.040

Guangda Shi, Jaeseung Lee, Smita Bhutda, Zienab Etwebi, Jesse Miller, Kasirajan Ayyanathan, Yue Li, David Nguyen, Yongqing Zhu, Wujuan Zhang, Aaron R Goldman, David C Schultz, Sara Cherry

{"title":"Uridine cytidine kinase 1 promotes phosphatidylcholine biosynthesis, facilitating SARS-CoV-2 infection.","authors":"Guangda Shi, Jaeseung Lee, Smita Bhutda, Zienab Etwebi, Jesse Miller, Kasirajan Ayyanathan, Yue Li, David Nguyen, Yongqing Zhu, Wujuan Zhang, Aaron R Goldman, David C Schultz, Sara Cherry","doi":"10.1016/j.molcel.2026.06.040","DOIUrl":"10.1016/j.molcel.2026.06.040","url":null,"abstract":"RNA viruses require diverse metabolic intermediates for replication, including nucleotides, which are synthesized through two pathways: de novo biosynthesis and salvage. De novo nucleotide biosynthesis is required for viral replication, but the role of nucleotide salvage is less clear. Genetic screening of purine and pyrimidine salvage pathways revealed a requirement for pyrimidine salvage in SARS-CoV-2 viral replication. Although both UCK1 and UCK2 catalyze the rate-limiting monophosphorylation of pyrimidines for pyrimidine salvage, we show that UCK2 is the major enzyme for cytoplasmic salvage of extracellular pyrimidines, functioning redundantly with de novo biosynthesis for RNA replication, and is thus dispensable for SARS-CoV-2 infection under conditions where de novo biosynthesis is active. In contrast, we find that UCK1 supports SARS-CoV-2 replication by specifically promoting nuclear cytidine triphosphate (CTP) synthesis for phosphatidylcholine (PC) biosynthesis, regulating peroxisomal lipid metabolism, and facilitating organelle interactions with double-membrane vesicles (DMVs), lipid structures required for SARS-CoV-2 RNA replication.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3258-3276.e6"},"PeriodicalIF":16.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549878","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