Molecular Systems Biology最新文献_第6页

Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability. 全基因组 CRISPR 筛选确定了野生型和突变型 p53 稳定性的新型调节器。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-04-05 DOI: 10.1038/s44320-024-00032-x

YiQing Lü, Tiffany Cho, Saptaparna Mukherjee, Carmen Florencia Suarez, Nicolas S Gonzalez-Foutel, Ahmad Malik, Sebastien Martinez, Dzana Dervovic, Robin Hyunseo Oh, Ellen Langille, Khalid N Al-Zahrani, Lisa Hoeg, Zhen Yuan Lin, Ricky Tsai, Geraldine Mbamalu, Varda Rotter, Patricia Ashton-Prolla, Jason Moffat, Lucia Beatriz Chemes, Anne-Claude Gingras, Moshe Oren, Daniel Durocher, Daniel Schramek

{"title":"Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.","authors":"YiQing Lü, Tiffany Cho, Saptaparna Mukherjee, Carmen Florencia Suarez, Nicolas S Gonzalez-Foutel, Ahmad Malik, Sebastien Martinez, Dzana Dervovic, Robin Hyunseo Oh, Ellen Langille, Khalid N Al-Zahrani, Lisa Hoeg, Zhen Yuan Lin, Ricky Tsai, Geraldine Mbamalu, Varda Rotter, Patricia Ashton-Prolla, Jason Moffat, Lucia Beatriz Chemes, Anne-Claude Gingras, Moshe Oren, Daniel Durocher, Daniel Schramek","doi":"10.1038/s44320-024-00032-x","DOIUrl":"10.1038/s44320-024-00032-x","url":null,"abstract":"Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"719-740"},"PeriodicalIF":9.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869136","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

Dietary fiber and gut bacteria shape infection susceptibility. 膳食纤维和肠道细菌影响感染易感性。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-23 DOI: 10.1038/s44320-024-00042-9

Aqsa Mohammed, Robert R Jenq

引用次数: 0

Diet-driven differential response of Akkermansia muciniphila modulates pathogen susceptibility. 饮食驱动的 Akkermansia muciniphila 不同反应调节了病原体的易感性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-14 DOI: 10.1038/s44320-024-00036-7

Mathis Wolter, Erica T Grant, Marie Boudaud, Nicholas A Pudlo, Gabriel V Pereira, Kathryn A Eaton, Eric C Martens, Mahesh S Desai

{"title":"Diet-driven differential response of Akkermansia muciniphila modulates pathogen susceptibility.","authors":"Mathis Wolter, Erica T Grant, Marie Boudaud, Nicholas A Pudlo, Gabriel V Pereira, Kathryn A Eaton, Eric C Martens, Mahesh S Desai","doi":"10.1038/s44320-024-00036-7","DOIUrl":"10.1038/s44320-024-00036-7","url":null,"abstract":"The erosion of the colonic mucus layer by a dietary fiber-deprived gut microbiota results in heightened susceptibility to an attaching and effacing pathogen, Citrobacter rodentium. Nevertheless, the questions of whether and how specific mucolytic bacteria aid in the increased pathogen susceptibility remain unexplored. Here, we leverage a functionally characterized, 14-member synthetic human microbiota in gnotobiotic mice to deduce which bacteria and functions are responsible for the pathogen susceptibility. Using strain dropouts of mucolytic bacteria from the community, we show that Akkermansia muciniphila renders the host more vulnerable to the mucosal pathogen during fiber deprivation. However, the presence of A. muciniphila reduces pathogen load on a fiber-sufficient diet, highlighting the context-dependent beneficial effects of this mucin specialist. The enhanced pathogen susceptibility is not owing to altered host immune or pathogen responses, but is driven by a combination of increased mucus penetrability and altered activities of A. muciniphila and other community members. Our study provides novel insights into the mechanisms of how discrete functional responses of the same mucolytic bacterium either resist or enhance enteric pathogen susceptibility.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"596-625"},"PeriodicalIF":8.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922754","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

An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors. 基于表观基因组的综合策略，对临床激酶抑制剂进行无偏见的功能分析。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-09 DOI: 10.1038/s44320-024-00040-x

Francesco Gualdrini, Stefano Rizzieri, Sara Polletti, Francesco Pileri, Yinxiu Zhan, Alessandro Cuomo, Gioacchino Natoli

{"title":"An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors.","authors":"Francesco Gualdrini, Stefano Rizzieri, Sara Polletti, Francesco Pileri, Yinxiu Zhan, Alessandro Cuomo, Gioacchino Natoli","doi":"10.1038/s44320-024-00040-x","DOIUrl":"10.1038/s44320-024-00040-x","url":null,"abstract":"More than 500 kinases are implicated in the control of most cellular process in mammals, and deregulation of their activity is linked to cancer and inflammatory disorders. 80 clinical kinase inhibitors (CKIs) have been approved for clinical use and hundreds are in various stages of development. However, CKIs inhibit other kinases in addition to the intended target(s), causing both enhanced clinical effects and undesired side effects that are only partially predictable based on in vitro selectivity profiling. Here, we report an integrative approach grounded on the use of chromatin modifications as unbiased, information-rich readouts of the functional effects of CKIs on macrophage activation. This approach exceeded the performance of transcriptome-based approaches and allowed us to identify similarities and differences among CKIs with identical intended targets, to recognize novel CKI specificities and to pinpoint CKIs that may be repurposed to control inflammation, thus supporting the utility of this strategy to improve selection and use of CKIs in clinical settings.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"626-650"},"PeriodicalIF":9.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897948","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

Integrated multiplexed assays of variant effect reveal determinants of catechol-O-methyltransferase gene expression. 变异效应的综合多重测定揭示了儿茶酚-O-甲基转移酶基因表达的决定因素。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-05-01 Epub Date: 2024-02-14 DOI: 10.1038/s44320-024-00018-9

Ian Hoskins, Shilpa Rao, Charisma Tante, Can Cenik

{"title":"Integrated multiplexed assays of variant effect reveal determinants of catechol-O-methyltransferase gene expression.","authors":"Ian Hoskins, Shilpa Rao, Charisma Tante, Can Cenik","doi":"10.1038/s44320-024-00018-9","DOIUrl":"10.1038/s44320-024-00018-9","url":null,"abstract":"Multiplexed assays of variant effect are powerful methods to profile the consequences of rare variants on gene expression and organismal fitness. Yet, few studies have integrated several multiplexed assays to map variant effects on gene expression in coding sequences. Here, we pioneered a multiplexed assay based on polysome profiling to measure variant effects on translation at scale, uncovering single-nucleotide variants that increase or decrease ribosome load. By combining high-throughput ribosome load data with multiplexed mRNA and protein abundance readouts, we mapped the cis-regulatory landscape of thousands of catechol-O-methyltransferase (COMT) variants from RNA to protein and found numerous coding variants that alter COMT expression. Finally, we trained machine learning models to map signatures of variant effects on COMT gene expression and uncovered both directional and divergent impacts across expression layers. Our analyses reveal expression phenotypes for thousands of variants in COMT and highlight variant effects on both single and multiple layers of expression. Our findings prompt future studies that integrate several multiplexed assays for the readout of gene expression.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"481-505"},"PeriodicalIF":9.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735666","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

Cellular energy regulates mRNA degradation in a codon-specific manner. 细胞能量以密码子特异性方式调节 mRNA 降解。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-05-01 Epub Date: 2024-03-15 DOI: 10.1038/s44320-024-00026-9

Pedro Tomaz da Silva, Yujie Zhang, Evangelos Theodorakis, Laura D Martens, Vicente A Yépez, Vicent Pelechano, Julien Gagneur

引用次数: 0

Mutational biases favor complexity increases in protein interaction networks after gene duplication. 基因复制后，突变偏差有利于蛋白质相互作用网络复杂性的增加。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-05-01 Epub Date: 2024-03-18 DOI: 10.1038/s44320-024-00030-z

Angel F Cisneros, Lou Nielly-Thibault, Saurav Mallik, Emmanuel D Levy, Christian R Landry

{"title":"Mutational biases favor complexity increases in protein interaction networks after gene duplication.","authors":"Angel F Cisneros, Lou Nielly-Thibault, Saurav Mallik, Emmanuel D Levy, Christian R Landry","doi":"10.1038/s44320-024-00030-z","DOIUrl":"10.1038/s44320-024-00030-z","url":null,"abstract":"Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"549-572"},"PeriodicalIF":8.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158556","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

Interrogation of RNA-protein interaction dynamics in bacterial growth. 细菌生长过程中 RNA 蛋白相互作用动力学的探索。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-05-01 Epub Date: 2024-03-26 DOI: 10.1038/s44320-024-00031-y

Mie Monti, Reyme Herman, Leonardo Mancini, Charlotte Capitanchik, Karen Davey, Charlotte S Dawson, Jernej Ule, Gavin H Thomas, Anne E Willis, Kathryn S Lilley, Eneko Villanueva

{"title":"Interrogation of RNA-protein interaction dynamics in bacterial growth.","authors":"Mie Monti, Reyme Herman, Leonardo Mancini, Charlotte Capitanchik, Karen Davey, Charlotte S Dawson, Jernej Ule, Gavin H Thomas, Anne E Willis, Kathryn S Lilley, Eneko Villanueva","doi":"10.1038/s44320-024-00031-y","DOIUrl":"10.1038/s44320-024-00031-y","url":null,"abstract":"Characterising RNA-protein interaction dynamics is fundamental to understand how bacteria respond to their environment. In this study, we have analysed the dynamics of 91% of the Escherichia coli expressed proteome and the RNA-interaction properties of 271 RNA-binding proteins (RBPs) at different growth phases. We find that 68% of RBPs differentially bind RNA across growth phases and characterise 17 previously unannotated proteins as bacterial RBPs including YfiF, a ncRNA-binding protein. While these new RBPs are mostly present in Proteobacteria, two of them are orthologs of human mitochondrial proteins associated with rare metabolic disorders. Moreover, we reveal novel RBP functions for proteins such as the chaperone HtpG, a new stationary phase tRNA-binding protein. For the first time, the dynamics of the bacterial RBPome have been interrogated, showcasing how this approach can reveal the function of uncharacterised proteins and identify critical RNA-protein interactions for cell growth which could inform new antimicrobial therapies.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"573-589"},"PeriodicalIF":9.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140294055","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

PIFiA: self-supervised approach for protein functional annotation from single-cell imaging data. PIFiA：从单细胞成像数据中获得蛋白质功能注释的自监督方法。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-05-01 Epub Date: 2024-03-12 DOI: 10.1038/s44320-024-00029-6

Anastasia Razdaibiedina, Alexander Brechalov, Helena Friesen, Mojca Mattiazzi Usaj, Myra Paz David Masinas, Harsha Garadi Suresh, Kyle Wang, Charles Boone, Jimmy Ba, Brenda Andrews

{"title":"PIFiA: self-supervised approach for protein functional annotation from single-cell imaging data.","authors":"Anastasia Razdaibiedina, Alexander Brechalov, Helena Friesen, Mojca Mattiazzi Usaj, Myra Paz David Masinas, Harsha Garadi Suresh, Kyle Wang, Charles Boone, Jimmy Ba, Brenda Andrews","doi":"10.1038/s44320-024-00029-6","DOIUrl":"10.1038/s44320-024-00029-6","url":null,"abstract":"Fluorescence microscopy data describe protein localization patterns at single-cell resolution and have the potential to reveal whole-proteome functional information with remarkable precision. Yet, extracting biologically meaningful representations from cell micrographs remains a major challenge. Existing approaches often fail to learn robust and noise-invariant features or rely on supervised labels for accurate annotations. We developed PIFiA (Protein Image-based Functional Annotation), a self-supervised approach for protein functional annotation from single-cell imaging data. We imaged the global yeast ORF-GFP collection and applied PIFiA to generate protein feature profiles from single-cell images of fluorescently tagged proteins. We show that PIFiA outperforms existing approaches for molecular representation learning and describe a range of downstream analysis tasks to explore the information content of the feature profiles. Specifically, we cluster extracted features into a hierarchy of functional organization, study cell population heterogeneity, and develop techniques to distinguish multi-localizing proteins and identify functional modules. Finally, we confirm new PIFiA predictions using a colocalization assay, suggesting previously unappreciated biological roles for several proteins. Paired with a fully interactive website ( https://thecellvision.org/pifia/ ), PIFiA is a resource for the quantitative analysis of protein organization within the cell.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"521-548"},"PeriodicalIF":9.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11066028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110698","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

Systematic identification of 20S proteasome substrates. 系统鉴定 20S 蛋白酶体底物。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-04-01 Epub Date: 2024-01-29 DOI: 10.1038/s44320-024-00015-y

Monika Pepelnjak, Rivkah Rogawski, Galina Arkind, Yegor Leushkin, Irit Fainer, Gili Ben-Nissan, Paola Picotti, Michal Sharon

{"title":"Systematic identification of 20S proteasome substrates.","authors":"Monika Pepelnjak, Rivkah Rogawski, Galina Arkind, Yegor Leushkin, Irit Fainer, Gili Ben-Nissan, Paola Picotti, Michal Sharon","doi":"10.1038/s44320-024-00015-y","DOIUrl":"10.1038/s44320-024-00015-y","url":null,"abstract":"For years, proteasomal degradation was predominantly attributed to the ubiquitin-26S proteasome pathway. However, it is now evident that the core 20S proteasome can independently target proteins for degradation. With approximately half of the cellular proteasomes comprising free 20S complexes, this degradation mechanism is not rare. Identifying 20S-specific substrates is challenging due to the dual-targeting of some proteins to either 20S or 26S proteasomes and the non-specificity of proteasome inhibitors. Consequently, knowledge of 20S proteasome substrates relies on limited hypothesis-driven studies. To comprehensively explore 20S proteasome substrates, we employed advanced mass spectrometry, along with biochemical and cellular analyses. This systematic approach revealed hundreds of 20S proteasome substrates, including proteins undergoing specific N- or C-terminal cleavage, possibly for regulation. Notably, these substrates were enriched in RNA- and DNA-binding proteins with intrinsically disordered regions, often found in the nucleus and stress granules. Under cellular stress, we observed reduced proteolytic activity in oxidized proteasomes, with oxidized protein substrates exhibiting higher structural disorder compared to unmodified proteins. Overall, our study illuminates the nature of 20S substrates, offering crucial insights into 20S proteasome biology.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"403-427"},"PeriodicalIF":9.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139576211","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