Molecular Cell最新文献_第2页

Alphavirus infection triggers selective cytoplasmic translocation of nuclear RBPs with moonlighting antiviral roles.

IF 14.5 1区生物学

Molecular Cell Pub Date : 2024-12-19 Epub Date: 2024-12-11 DOI: 10.1016/j.molcel.2024.11.015

Wael Kamel, Vincenzo Ruscica, Azman Embarc-Buh, Zaydah R de Laurent, Manuel Garcia-Moreno, Yana Demyanenko, Richard J Orton, Marko Noerenberg, Meghana Madhusudhan, Louisa Iselin, Aino I Järvelin, Maximilian Hannan, Eduardo Kitano, Samantha Moore, Andres Merits, Ilan Davis, Shabaz Mohammed, Alfredo Castello

{"title":"Alphavirus infection triggers selective cytoplasmic translocation of nuclear RBPs with moonlighting antiviral roles.","authors":"Wael Kamel, Vincenzo Ruscica, Azman Embarc-Buh, Zaydah R de Laurent, Manuel Garcia-Moreno, Yana Demyanenko, Richard J Orton, Marko Noerenberg, Meghana Madhusudhan, Louisa Iselin, Aino I Järvelin, Maximilian Hannan, Eduardo Kitano, Samantha Moore, Andres Merits, Ilan Davis, Shabaz Mohammed, Alfredo Castello","doi":"10.1016/j.molcel.2024.11.015","DOIUrl":"10.1016/j.molcel.2024.11.015","url":null,"abstract":"RNA is a central molecule for viruses; however, the interactions that viral RNA (vRNA) establishes with the host cell is only starting to be elucidated. Here, we determine the ribonucleoprotein (RNP) composition of the prototypical arthropod-borne Sindbis virus (SINV). We show that SINV RNAs engage with hundreds of cellular proteins, including a group of nuclear RNA-binding proteins (RBPs) with unknown roles in infection. We demonstrate that these nuclear RBPs are selectively translocated to the cytoplasm after infection, where they accumulate in the viral replication organelles (ROs). These nuclear RBPs strongly suppress viral gene expression, with activities spanning viral species and families. Particularly, the U2 small nuclear RNP (snRNP) emerges as an antiviral complex, with both its U2 small nuclear RNA (snRNA) and protein components contributing to the recognition of the vRNA and the antiviral phenotype. These results suggest that the U2 snRNP has RNA-driven antiviral activity in a mechanism reminiscent of the RNAi pathway.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"4896-4911.e7"},"PeriodicalIF":14.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791756","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

Quantitative profiling of human translation initiation reveals elements that potently regulate endogenous and therapeutically modified mRNAs

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-19 DOI: 10.1016/j.molcel.2024.11.030

Cole J.T. Lewis, Li H. Xie, Shivani Milind Bhandarkar, Danni Jin, Kyrillos Abdallah, Austin S. Draycott, Yixuan Chen, Carson C. Thoreen, Wendy V. Gilbert

{"title":"Quantitative profiling of human translation initiation reveals elements that potently regulate endogenous and therapeutically modified mRNAs","authors":"Cole J.T. Lewis, Li H. Xie, Shivani Milind Bhandarkar, Danni Jin, Kyrillos Abdallah, Austin S. Draycott, Yixuan Chen, Carson C. Thoreen, Wendy V. Gilbert","doi":"10.1016/j.molcel.2024.11.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.030","url":null,"abstract":"mRNA therapeutics offer a potentially universal strategy for the efficient development and delivery of therapeutic proteins. Current mRNA vaccines include chemically modified nucleotides to reduce cellular immunogenicity. Here, we develop an efficient, high-throughput method to measure human translation initiation on therapeutically modified as well as endogenous RNAs. Using systems-level biochemistry, we quantify ribosome recruitment to tens of thousands of human 5′ untranslated regions (UTRs) including alternative isoforms and identify sequences that mediate 200-fold effects. We observe widespread effects of coding sequences on translation initiation and identify small regulatory elements of 3–6 nucleotides that are sufficient to potently affect translational output. Incorporation of N1-methylpseudouridine (m1Ψ) selectively enhances translation by specific 5′ UTRs that we demonstrate surpass those of current mRNA vaccines. Our approach is broadly applicable to dissecting mechanisms of human translation initiation and engineering more potent therapeutic mRNAs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"32 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849563","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

eEF2K regulates pain through translational control of BDNF

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-17 DOI: 10.1016/j.molcel.2024.11.023

Patrick R. Smith, Guadalupe Garcia, Angela R. Meyer, Alexey G. Ryazanov, Tao Ma, Sarah Loerch, Zachary T. Campbell

引用次数: 0

MYO1F positions cGAS on the plasma membrane to ensure full and functional signaling

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-17 DOI: 10.1016/j.molcel.2024.11.026

Heping Wang, Zhihui Cui, Wanwei Sun, Ming Yi, Yuheng Cheng, Yunpeng Zhang, Yanyun Du, Ting Pan, Ru Gao, Lingyun Feng, Bo Zeng, Guoling Huang, Yangyang Li, Yuan Wang, Cun-jin Zhang, Ruirui He, Chenhui Wang

{"title":"MYO1F positions cGAS on the plasma membrane to ensure full and functional signaling","authors":"Heping Wang, Zhihui Cui, Wanwei Sun, Ming Yi, Yuheng Cheng, Yunpeng Zhang, Yanyun Du, Ting Pan, Ru Gao, Lingyun Feng, Bo Zeng, Guoling Huang, Yangyang Li, Yuan Wang, Cun-jin Zhang, Ruirui He, Chenhui Wang","doi":"10.1016/j.molcel.2024.11.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.026","url":null,"abstract":"Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) detects viral or endogenous DNA, activating the innate immune response to infections and autoimmune diseases. Upon binding to double-stranded DNA, cGAS synthesizes 2′3′ cGMP-AMP, which triggers type I interferon production. Besides its presence in the cytosol and nucleus, cGAS is found at the plasma membrane, although its significance remains unclear. Here, we report that cGAS associates with myosin 1F (MYO1F) at the plasma membrane of human and mouse macrophages. During viral infection, phosphorylation of MYO1F by spleen-associated tyrosine kinase (SYK) facilitates the recruitment of lysine acetyltransferase 2A (KAT2A), which acetylates cGAS at lysine residues 421, 292, and 131, essential for its activation. Moreover, membrane-localized cGAS is crucial for signaling activation and type I interferon production triggered by virus-cell fusion due to Mn2+ release from organelles. Our results highlight the importance of MYO1F-mediated cGAS localization for its full activation in response to viral infection.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"60 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832851","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

Interchromosomal contacts between regulatory regions trigger stable transgenerational epigenetic inheritance in Drosophila

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-11 DOI: 10.1016/j.molcel.2024.11.021

Maximilian H. Fitz-James, Gonzalo Sabarís, Peter Sarkies, Frédéric Bantignies, Giacomo Cavalli

{"title":"Interchromosomal contacts between regulatory regions trigger stable transgenerational epigenetic inheritance in Drosophila","authors":"Maximilian H. Fitz-James, Gonzalo Sabarís, Peter Sarkies, Frédéric Bantignies, Giacomo Cavalli","doi":"10.1016/j.molcel.2024.11.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.021","url":null,"abstract":"Non-genetic information can be inherited across generations in a process known as transgenerational epigenetic inheritance (TEI). In Drosophila, hemizygosity of the Fab-7 regulatory element triggers inheritance of the histone mark H3K27me3 at a homologous locus on another chromosome, resulting in heritable epigenetic differences in eye color. Here, by mutating transcription factor binding sites within the Fab-7 element, we demonstrate the importance of the proteins pleiohomeotic and GAGA factor in the establishment and maintenance of TEI. We show that these proteins function by recruiting the polycomb repressive complex 2 and by mediating interchromosomal chromatin contacts between Fab-7 and its homologous locus, respectively. Using an in vivo synthetic biology system to induce them, we then show that chromatin contacts alone can establish TEI, providing a mechanism by which hemizygosity of one locus can establish epigenetic memory at another distant locus in trans through chromatin contacts.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"55 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804890","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

CRL3ARMC5 ubiquitin ligase and Integrator phosphatase form parallel mechanisms to control early stages of RNA Pol II transcription

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-11 DOI: 10.1016/j.molcel.2024.11.024

Roberta Cacioppo, Alexander Gillis, Iván Shlamovitz, Andrew Zeller, Daniela Castiblanco, Alastair Crisp, Benjamin Haworth, Angela Arabiotorre, Pegah Abyaneh, Yu Bao, Julian E. Sale, Scott Berry, Ana Tufegdžić Vidaković

{"title":"CRL3ARMC5 ubiquitin ligase and Integrator phosphatase form parallel mechanisms to control early stages of RNA Pol II transcription","authors":"Roberta Cacioppo, Alexander Gillis, Iván Shlamovitz, Andrew Zeller, Daniela Castiblanco, Alastair Crisp, Benjamin Haworth, Angela Arabiotorre, Pegah Abyaneh, Yu Bao, Julian E. Sale, Scott Berry, Ana Tufegdžić Vidaković","doi":"10.1016/j.molcel.2024.11.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.024","url":null,"abstract":"Control of RNA polymerase II (RNA Pol II) through ubiquitylation is essential for the DNA-damage response. Here, we reveal a distinct ubiquitylation pathway in human cells, mediated by CRL3ARMC5, that targets excessive and defective RNA Pol II molecules at the initial stages of the transcription cycle. Upon ARMC5 loss, RNA Pol II accumulates in the free pool and in the promoter-proximal zone but is not permitted into elongation. We identify Integrator subunit 8 (INTS8) as a gatekeeper preventing the release of excess RNA Pol II molecules into gene bodies. Combined loss of ARMC5 and INTS8 has detrimental effects on cell growth and results in the uncontrolled release of excessive RNA Pol II complexes into early elongation, many of which are transcriptionally incompetent and fail to reach the ends of genes. These findings uncover CRL3ARMC5 and Integrator as two distinct pathways acting in parallel to monitor the quantity and quality of transcription complexes before they are licensed into elongation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"204 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804891","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

Circular RNAs trigger nonsense-mediated mRNA decay

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-11 DOI: 10.1016/j.molcel.2024.11.022

Sung Ho Boo, Min-Kyung Shin, Hyun Jung Hwang, Hyeonseo Hwang, Sunwoo Chang, TaeSoo Kim, Daehyun Baek, Yoon Ki Kim

{"title":"Circular RNAs trigger nonsense-mediated mRNA decay","authors":"Sung Ho Boo, Min-Kyung Shin, Hyun Jung Hwang, Hyeonseo Hwang, Sunwoo Chang, TaeSoo Kim, Daehyun Baek, Yoon Ki Kim","doi":"10.1016/j.molcel.2024.11.022","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.022","url":null,"abstract":"Circular RNAs (circRNAs) are covalently closed single-stranded RNAs produced predominantly through a back-splicing process. They play regulatory roles in various biological and physiological processes; however, the molecular mechanisms by which circRNAs operate remain unclear. Herein, we demonstrate that circRNAs facilitate rapid mRNA degradation through RNA-RNA interactions between circRNAs and the 3′ untranslated regions (3′ UTRs) of mRNAs. This interaction positions the exon-junction complexes (EJCs), deposited onto circRNAs by back-splicing, near the 3′ UTRs of the mRNAs, thereby leading to EJC-dependent nonsense-mediated mRNA decay (NMD), a process we describe as circRNA-induced NMD (circNMD). Our transcriptomic analysis reveals hundreds of potential circNMD candidates, and the biological importance of circNMD in cellular apoptosis is validated. We also demonstrate that exogenously expressed circRNAs designed to interact with the 3′ UTRs of endogenous mRNAs significantly downregulate the mRNA levels. Collectively, our observations provide compelling molecular evidence for circNMD and its potential therapeutic application in selective mRNA downregulation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"71 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142804889","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

Epitranscriptomic rRNA fingerprinting reveals tissue-of-origin and tumor-specific signatures 表观转录组 rRNA 指纹图谱揭示了原发组织和肿瘤特异性特征

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-10 DOI: 10.1016/j.molcel.2024.11.014

Ivan Milenkovic, Sonia Cruciani, Laia Llovera, Morghan C. Lucas, Rebeca Medina, Cornelius Pauli, Daniel Heid, Thomas Muley, Marc A. Schneider, Laura V. Klotz, Michael Allgäuer, Ruben Lattuca, Denis L.J. Lafontaine, Carsten Müller-Tidow, Eva Maria Novoa

{"title":"Epitranscriptomic rRNA fingerprinting reveals tissue-of-origin and tumor-specific signatures","authors":"Ivan Milenkovic, Sonia Cruciani, Laia Llovera, Morghan C. Lucas, Rebeca Medina, Cornelius Pauli, Daniel Heid, Thomas Muley, Marc A. Schneider, Laura V. Klotz, Michael Allgäuer, Ruben Lattuca, Denis L.J. Lafontaine, Carsten Müller-Tidow, Eva Maria Novoa","doi":"10.1016/j.molcel.2024.11.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.014","url":null,"abstract":"Mammalian ribosomal RNA (rRNA) molecules are highly abundant RNAs, decorated with over 220 rRNA modifications. Previous works have shown that some rRNA modification types can be dynamically regulated; however, how and when the mammalian rRNA modification landscape is remodeled remains largely unexplored. Here, we employ direct RNA sequencing to chart the human and mouse rRNA epitranscriptome across tissues, developmental stages, cell types, and disease. Our analyses reveal multiple rRNA sites that are differentially modified in a tissue- and/or developmental stage-specific manner, including previously unannotated modified sites. We demonstrate that rRNA modification patterns can be used for tissue and cell-type identification, which we hereby term “epitranscriptomic fingerprinting.” We then explore rRNA modification patterns in normal-tumor matched samples from lung cancer patients, finding that epitranscriptomic fingerprinting accurately classifies clinical samples into normal and tumor groups from only 250 reads per sample, demonstrating the potential of rRNA modifications as diagnostic biomarkers.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"9 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797523","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

TBP bookmarks and preserves neural stem cell fate memory by orchestrating local chromatin architecture TBP通过协调局部染色质结构书签和保存神经干细胞命运记忆

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-10 DOI: 10.1016/j.molcel.2024.11.019

Yuying Shen, Kun Liu, Jie Liu, Jingwen Shen, Tongtong Ye, Runxiang Zhao, Rulan Zhang, Yan Song

{"title":"TBP bookmarks and preserves neural stem cell fate memory by orchestrating local chromatin architecture","authors":"Yuying Shen, Kun Liu, Jie Liu, Jingwen Shen, Tongtong Ye, Runxiang Zhao, Rulan Zhang, Yan Song","doi":"10.1016/j.molcel.2024.11.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.019","url":null,"abstract":"Mitotic bookmarking has been posited as an important strategy for cells to faithfully propagate their fate memory through cell generations. However, the physiological significance and regulatory mechanisms of mitotic bookmarking in neural development remain unexplored. Here, we identified TATA-binding protein (TBP) as a crucial mitotic bookmarker for preserving the fate memory of Drosophila neural stem cells (NSCs). Phosphorylation by the super elongation complex (SEC) is important for TBP to retain as discrete foci at mitotic chromosomes of NSCs to effectively transmit their fate memory. TBP depletion leads to drastic NSC loss, whereas TBP overexpression enhances the ability of SEC to induce neural progenitor dedifferentiation and tumorigenesis. Importantly, TBP achieves its mitotic retention through recruiting the chromatin remodeler EP400, which in turn increases local chromatin accessibility via depositing H2A.Z. Thus, local chromatin remodeling ensures mitotic bookmarking, which may represent a general principle underlying the preservation of cell fate memory.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"36 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142797522","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

Lactylation as a post-translational regulator of cGAS and immunity

IF 16 1区生物学

Molecular Cell Pub Date : 2024-12-05 DOI: 10.1016/j.molcel.2024.11.018

Haipeng Liu, Baoxue Ge

引用次数: 0