Molecular Cell最新文献

Salmonella effector SteE reprograms the macrophage regulatory network to drive specific hyperactivation of STAT3 target genes. 沙门氏菌效应物SteE重编程巨噬细胞调控网络以驱动STAT3靶基因的特异性超激活。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-08 DOI: 10.1016/j.molcel.2026.04.012

Ines Diaz-Del-Olmo, Paul A O'Sullivan, Thomas S Wilson, Andrea Majstorovic, Georgia Miller, Sayaka Shizukuishi, Adriana Stypulkowska, Ioanna Panagi, Krzysztof Grzymajlo, Michinaga Ogawa, Jelena S Bezbradica, Peter W S Hill, Teresa L M Thurston

{"title":"Salmonella effector SteE reprograms the macrophage regulatory network to drive specific hyperactivation of STAT3 target genes.","authors":"Ines Diaz-Del-Olmo, Paul A O'Sullivan, Thomas S Wilson, Andrea Majstorovic, Georgia Miller, Sayaka Shizukuishi, Adriana Stypulkowska, Ioanna Panagi, Krzysztof Grzymajlo, Michinaga Ogawa, Jelena S Bezbradica, Peter W S Hill, Teresa L M Thurston","doi":"10.1016/j.molcel.2026.04.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.04.012","url":null,"abstract":"The ability of Salmonella Typhimurium to exploit macrophages as a niche for survival, replication, and dissemination is central to its pathogenesis. The effector SteE, which polarizes macrophages into an anti-inflammatory state, is critical during invasive disease. SteE operates via an unprecedented mechanism, reprogramming the host serine/threonine kinase GSK3 to perform tyrosyl-directed phosphorylation of neosubstrates, including the immune transcription factors STAT1 and STAT3. Here, we demonstrate that SteE-driven transcriptional reprogramming relies critically and specifically on STAT3 phosphorylation and DNA binding. By activating STAT3 via a non-canonical pathway, bypassing endogenous negative feedback mechanisms, SteE drives hyperactivation of STAT3 target genes, surpassing the effects of canonical IL-10 signaling. Hyperactivation correlates with elevated phosphorylated STAT3 in the macrophage nucleus and coordinated chromatin remodeling at STAT3 target loci. Overall, our study illustrates how hijacking of a signaling pathway by SteE dramatically reshapes the macrophage gene regulatory network to enhance Salmonella immune evasion.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864290","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

5'-Triphosphate guanosine RNAs recruit GTP-binding proteins to suppress RIG-I/IFN type I signaling. 5'-三磷酸鸟苷rna募集gtp结合蛋白抑制RIG-I/IFN I型信号。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-08 DOI: 10.1016/j.molcel.2026.04.014

Magdalena Wolczyk, Jacek Szymanski, Ivan Trus, Zara Naz, Nathalie Idlin, Michal Lechowski, Emilia Baranowska, Alicja Bis, Jakub Stanislaw Nowak, Tola Tame, Justyna Jackiewicz, Elzbieta Nowak, Christine Wuebben, Gunther Hartmann, Juri Rappsilber, Gracjan Michlewski

{"title":"5'-Triphosphate guanosine RNAs recruit GTP-binding proteins to suppress RIG-I/IFN type I signaling.","authors":"Magdalena Wolczyk, Jacek Szymanski, Ivan Trus, Zara Naz, Nathalie Idlin, Michal Lechowski, Emilia Baranowska, Alicja Bis, Jakub Stanislaw Nowak, Tola Tame, Justyna Jackiewicz, Elzbieta Nowak, Christine Wuebben, Gunther Hartmann, Juri Rappsilber, Gracjan Michlewski","doi":"10.1016/j.molcel.2026.04.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.04.014","url":null,"abstract":"The interferon (IFN) response is crucial for antiviral activity, but excessive activation can contribute to tissue damage and autoimmune disorders. The cytoplasmic receptor retinoic acid-inducible gene I (RIG-I) detects viral double-stranded RNAs (dsRNAs) and endogenous RNA polymerase III (RNA Pol III) transcripts carrying a 5'-triphosphate (5'-ppp) moiety, triggering IRF3 phosphorylation and IFN response. Many viral RNAs initiate with 5'-triphosphate adenosine (5'-pppA), whereas most endogenous RNA Pol III transcripts in higher eukaryotes start with 5'-triphosphate guanosine (5'-pppG), yet no reason for this bias is known. Here, we show that 5'-pppA dsRNAs trigger stronger RIG-I/IFN responses than 5'-pppG dsRNAs, despite comparable RIG-I stimulation in vitro. Using RNA pull-down and mass spectrometry, we identify GTP-binding proteins that preferentially interact with 5'-pppG dsRNAs. Guanosine supplementation, which increases intracellular GTP levels, decreases the immunogenic difference between 5'-pppG and 5'-pppA dsRNAs. Our findings provide insights into sequence-dependent activation of the RIG-I/IFN pathway, with implications for evolutionary pressures on RNA sequences, RNA-driven autoimmunity, viral immunogenicity, and the rational design of RNA therapeutics.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864207","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

Apical localization of RNA polymerases modulates transcription dynamics and supercoiling domains revealed by cryo-ET. RNA聚合酶的顶端定位调节转录动力学和超卷曲结构域。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-08 DOI: 10.1016/j.molcel.2026.04.013

Meng Zhang, Cristhian Cañari-Chumpitaz, Jianfang Liu, Bibiana Onoa, Sinead de Cleir, Enze Cheng, Katherinne I Requejo, Carlos Bustamante

{"title":"Apical localization of RNA polymerases modulates transcription dynamics and supercoiling domains revealed by cryo-ET.","authors":"Meng Zhang, Cristhian Cañari-Chumpitaz, Jianfang Liu, Bibiana Onoa, Sinead de Cleir, Enze Cheng, Katherinne I Requejo, Carlos Bustamante","doi":"10.1016/j.molcel.2026.04.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2026.04.013","url":null,"abstract":"Protein interactions with canonical B-form DNA are well characterized, yet the effect of torsionally constrained DNA on these interactions-ubiquitous in cells-remains underexplored. Using cryo-electron tomography (cryo-ET), we 3D-reconstructed entire negatively supercoiled DNA substrates bound to active RNA polymerase (RNAP), revealing diverse DNA supercoiling conformations and their interplay with transcription. RNAP preferentially localizes at plectoneme apices in a swiveled, pause-prone state. RNAP, along with other DNA-melting proteins such as dCas9, can act as torsional roadblocks that segregate \"twin-supercoiling domains\" during active transcription, independent of external DNA/RNAP tethering. Co-transcribing RNAPs further intensify this domain separation: tandem-oriented RNAPs relieve negative supercoiling more effectively than opposing ones and promote greater RNAP accumulation and enhanced elongation, both in vitro and in vivo. Topoisomerase I relieves torsional stress and facilitates RNAP escape from apical stalls, thereby supporting apical transcription regulation. Together, these findings support a load-and-release mechanism at plectoneme apices that may underlie supercoiling-dependent transcriptional bursting.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864267","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 discovery of 5mC-selective deaminases and their application to ultra-sensitive direct sequencing of methylated sites at base resolution. 5mc选择性脱氨酶的发现及其在碱基分辨率下甲基化位点超灵敏直接测序中的应用。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-07 Epub Date: 2026-04-16 DOI: 10.1016/j.molcel.2026.03.027

Weiwei Yang, Yan-Jiun Lee, Rebekah M B Silva, Amanda DeLiberto, Colleen E Yancey, Daria McCallum, Jackson A Buss, Rey Moncion, Jennifer L Ong, Megumu Mabuchi, David M Hough, Peter R Weigele, Laurence M Ettwiller

{"title":"The discovery of 5mC-selective deaminases and their application to ultra-sensitive direct sequencing of methylated sites at base resolution.","authors":"Weiwei Yang, Yan-Jiun Lee, Rebekah M B Silva, Amanda DeLiberto, Colleen E Yancey, Daria McCallum, Jackson A Buss, Rey Moncion, Jennifer L Ong, Megumu Mabuchi, David M Hough, Peter R Weigele, Laurence M Ettwiller","doi":"10.1016/j.molcel.2026.03.027","DOIUrl":"10.1016/j.molcel.2026.03.027","url":null,"abstract":"Mining phages for new enzymatic activities continues to be important for the development of new tools for biotechnology. In this study, we used MetaGPA-a method linking genotype to phenotype in metagenomic data-to identify deoxycytidine deaminases, a protein family highly associated with cytosine modifications in metaviromes. Unexpectedly, a subset of these deaminases exhibited a preference for 5-methylcytosine (5mC) over cytosine (C) in both mononucleotide and single-stranded DNA substrates. In a methylome-sequencing workflow, deamination of 5mC by these enzymes enabled direct conversion of methylated cytosine while completely eliminating any background deamination of unmodified cytosine. This direct conversion allows for precise identification of methylated sites at single-base resolution with unmatched sensitivity enabling broad applications for the simultaneous sequencing of genome and methylome.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1598-1613.e11"},"PeriodicalIF":16.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717341","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

PDS5 proteins control genome architecture by limiting the lifetime of cohesin-NIPBL complexes. PDS5蛋白通过限制黏结素- nipbl复合物的寿命来控制基因组结构。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-07 Epub Date: 2026-04-23 DOI: 10.1016/j.molcel.2026.03.025

Gordana Wutz, Iain F Davidson, Edward J Banigan, Roman R Stocsits, Ryotaro Kawasumi, Wen Tang, Kota Nagasaka, Lorenzo Costantino, Ralf Jansen, Kouji Hirota, Dana Branzei, Leonid A Mirny, Jan-Michael Peters

{"title":"PDS5 proteins control genome architecture by limiting the lifetime of cohesin-NIPBL complexes.","authors":"Gordana Wutz, Iain F Davidson, Edward J Banigan, Roman R Stocsits, Ryotaro Kawasumi, Wen Tang, Kota Nagasaka, Lorenzo Costantino, Ralf Jansen, Kouji Hirota, Dana Branzei, Leonid A Mirny, Jan-Michael Peters","doi":"10.1016/j.molcel.2026.03.025","DOIUrl":"10.1016/j.molcel.2026.03.025","url":null,"abstract":"Cohesin-NIPBL complexes extrude genomic DNA into loops that are constrained by CTCF boundaries. This process has important regulatory functions and weakens the separation between euchromatic and heterochromatic compartments. Cohesin can also bind PDS5 proteins, which do not support loop extrusion but are required for the formation of CTCF boundaries. How PDS5 proteins perform this function is unknown. Here we show, by in vitro single-molecule imaging, that human PDS5 proteins stop loop extrusion by facilitating the dissociation of NIPBL from cohesin. Hi-C experiments suggest that this function is required for the establishment of CTCF boundaries in cells. In silico modeling indicates that PDS5 proteins enable the separation between compartments by limiting cohesin's velocity and chromatin residence time. The degree of this compartmentalization depends on the frequency with which chromatin is extruded relative to the time it takes for compartments to form. These results identify PDS5 proteins as key regulators of genome organization.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1614-1634.e10"},"PeriodicalIF":16.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777122","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

Mutual antagonism between PRC1 condensates and SWI/SNF in chromatin regulation. PRC1缩合物与SWI/SNF在染色质调控中的相互拮抗作用。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-07 Epub Date: 2026-04-24 DOI: 10.1016/j.molcel.2026.04.001

Stefan Niekamp, Sharon K Marr, Rebecca Sanon, Philipp C Schneider, Radhika Subramanian, Robert E Kingston

{"title":"Mutual antagonism between PRC1 condensates and SWI/SNF in chromatin regulation.","authors":"Stefan Niekamp, Sharon K Marr, Rebecca Sanon, Philipp C Schneider, Radhika Subramanian, Robert E Kingston","doi":"10.1016/j.molcel.2026.04.001","DOIUrl":"10.1016/j.molcel.2026.04.001","url":null,"abstract":"Opposing activities of conserved chromatin regulatory complexes, such as the Polycomb repressive complex 1 (PRC1) and the activating chromatin remodeler switch/sucrose non-fermentable (SWI/SNF), play critical roles in regulating gene expression during development and differentiation. The mechanisms by which these complexes compete to regulate chromatin states remain poorly understood. We combine single-molecule analysis and genomic approaches in cultured cells to demonstrate that the condensate-forming properties of PRC1 play an important role in excluding SWI/SNF from chromatin. Consistently, PRC1 compositions with higher condensate-forming propensity are more effective in preventing SWI/SNF binding. Conversely, SWI/SNF-bound chromatin significantly reduces PRC1 binding and subsequent condensate formation. Notably, SWI/SNF can suppress PRC1 condensate formation in an ATP-hydrolysis-independent manner. We propose that the condensate properties of different PRC1 compositions drive mutual PRC1-SWI/SNF antagonism to properly balance these competing regulatory activities during development.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1673-1690.e15"},"PeriodicalIF":16.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777093","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 time-resolved atlas of histone modifications during mitotic entry. 有丝分裂进入时组蛋白修饰的时间分辨图谱。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-07 Epub Date: 2026-04-23 DOI: 10.1016/j.molcel.2026.03.038

Natalia Y Kochanova, Moonmoon Deb, Marco Borsò, Shaun Webb, Ipek Ustun, Kumiko Samejima, Ignasi Forne, Itaru Samejima, Caitlin Reid, Linfeng Xie, James R Paulson, Axel Imhof, William C Earnshaw

{"title":"A time-resolved atlas of histone modifications during mitotic entry.","authors":"Natalia Y Kochanova, Moonmoon Deb, Marco Borsò, Shaun Webb, Ipek Ustun, Kumiko Samejima, Ignasi Forne, Itaru Samejima, Caitlin Reid, Linfeng Xie, James R Paulson, Axel Imhof, William C Earnshaw","doi":"10.1016/j.molcel.2026.03.038","DOIUrl":"10.1016/j.molcel.2026.03.038","url":null,"abstract":"Mitotic chromosome formation is essential for faithful chromosome segregation in metazoans. Although condensin complexes are critical for the formation of rod-shaped mitotic chromosomes, histone phosphorylation and deacetylation have been proposed to contribute to a further 2- to 4-fold reduction in mitotic chromatin volume. Here, we employ high-resolution mass spectrometry to determine the kinetics of histone modifications in cell cultures undergoing highly synchronous mitotic entry. Our analysis reveals three temporally distinct programs of histone H3 phosphorylation on T3, S10, and S28 that could differentially regulate the association of readers with chromatin via methyl-phos switching. Mass spectrometry, quantitative chromatin immunoprecipitation sequencing (ChIP-seq), ChIP-qPCR, and immunofluorescence analyses reveal that H3 T3 phosphorylation is a mitosis-specific marker of heterochromatin, whose deposition requires H3K9me3. Finally, we show that histone acetylation undergoes only modest changes as rod-shaped chromosomes form during unperturbed mitotic entry. Thus, deacetylation does not drive mitotic chromosome formation. The mechanism of condensin-independent chromatin compaction in mitosis remains unexplained.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1653-1672.e9"},"PeriodicalIF":16.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777103","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

Enzyme agglomerates change cytoplasmic fluidity. 酶凝聚改变细胞质的流动性。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-07 DOI: 10.1016/j.molcel.2026.04.011

Remy Colin, Victor Sourjik

引用次数: 0

PARP1 suppression drives ROS resistance in aneuploid cancer cells. PARP1抑制驱动非整倍体癌细胞的ROS抗性。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-07 Epub Date: 2026-04-30 DOI: 10.1016/j.molcel.2026.04.006

Pan Cheng, Angela Mermerian-Baghdassarian, Yufeng Wang, Ze Chen, Helberth M Quysbertf, Pradeep Singh Cheema, Joseph C Mays, Xin Zhao, Lizabeth Katsnelson, Sally Mei, Rohini Shrivastava, Mirna Bulatovic, Jiehui Deng, Markus Schober, Kwok-Kin Wong, Teresa Davoli

{"title":"PARP1 suppression drives ROS resistance in aneuploid cancer cells.","authors":"Pan Cheng, Angela Mermerian-Baghdassarian, Yufeng Wang, Ze Chen, Helberth M Quysbertf, Pradeep Singh Cheema, Joseph C Mays, Xin Zhao, Lizabeth Katsnelson, Sally Mei, Rohini Shrivastava, Mirna Bulatovic, Jiehui Deng, Markus Schober, Kwok-Kin Wong, Teresa Davoli","doi":"10.1016/j.molcel.2026.04.006","DOIUrl":"10.1016/j.molcel.2026.04.006","url":null,"abstract":"Aneuploidy is common in cancer and has been implicated in promoting tumor progression, yet the underlying mechanisms remain poorly understood. By generating models of aneuploidy, we found that aneuploidy confers resistance to reactive oxygen species (ROS)-mediated cell death, independent of the specific chromosomes gained or lost. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1) is suppressed in aneuploid cells, which inhibits PARP1-mediated cell death (parthanatos). We validated aneuploidy-associated PARP1 suppression across 15 cell models and human tumors, with pronounced effects in metastatic tumors. Importantly, PARP1 downregulation promotes tumor metastasis while PARP1 upregulation suppresses it. Through a genome-wide CRISPR screen and functional validation, we identified the transcription factor CCAAT/enhancer-binding protein beta (CEBPB) as a mediator of PARP1 downregulation and ROS resistance in aneuploid cells. Lysosomal dysfunction serves as the upstream activator of CEBPB in aneuploid cells. We propose that aneuploidy-driven CEBPB activation suppresses PARP1, fostering ROS resistance and cancer progression.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"1742-1761.e19"},"PeriodicalIF":16.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817814","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

Extracellular alkalinization boosts plant immunity. 细胞外碱化增强植物免疫力。

IF 16.6 1区生物学

Molecular Cell Pub Date : 2026-05-07 DOI: 10.1016/j.molcel.2026.04.005

Yuhang Ming, Wen Song

引用次数: 0