Molecular Systems Biology最新文献_第4页

A discovery platform for identification of host-induced bacterial biosensors from diverse sources. 一个发现平台，用于鉴定来自不同来源的宿主诱导的细菌生物传感器。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 Epub Date: 2025-06-09 DOI: 10.1038/s44320-025-00123-3

Clare M Robinson, David Carreño, Tim Weber, Yangyumeng Chen, David T Riglar

{"title":"A discovery platform for identification of host-induced bacterial biosensors from diverse sources.","authors":"Clare M Robinson, David Carreño, Tim Weber, Yangyumeng Chen, David T Riglar","doi":"10.1038/s44320-025-00123-3","DOIUrl":"10.1038/s44320-025-00123-3","url":null,"abstract":"Synthetic biology approaches such as whole-cell biosensing and 'sense-and-respond' therapeutics aim to enlist the vast sensing repertoire of gut microbes to drive cutting-edge clinical and research applications. However, well-characterised circuit components that sense health- and disease-relevant conditions within the gut remain limited. Here, we extend the flexibility and power of a biosensor screening platform using bacterial memory circuits. We construct libraries of sensory components sourced from diverse gut bacteria using a bespoke two-component system identification and cloning pipeline. Tagging unique strains using a hypervariable DNA barcode enables parallel tracking of thousands of unique clones, corresponding to ~150 putative biosensors, in a single experiment. Evaluating sensor activity and performance heterogeneity across various in vitro and in vivo conditions using mouse models, we identify several biosensors of interest. Validated hits include biosensors with relevance for autonomous control of synthetic functions within the mammalian gut and for non-invasive monitoring of inflammatory disease using faecal sampling. This approach will promote rapid biosensor engineering to advance the development of synthetic biology tools for deployment within complex environments.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1237-1262"},"PeriodicalIF":7.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258609","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

Systems approach identifies monocyte imbalance in symptomatic and asymptomatic P. vivax malaria. 系统方法确定有症状和无症状间日疟原虫疟疾的单核细胞失衡。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-19 DOI: 10.1038/s44320-025-00135-z

Stephanie I Studniberg, Mariam Bafit, Lisa J Ioannidis, Matthew J Worley, Leily Trianty, Retno A S Utami, Agatha M Puspitasari, Dwi Apriyanti, Farah N Coutrier, Jeanne R Poespoprodjo, Enny Kenangalem, Benediktus Andries, Pak Prayoga, Ric N Price, Rintis Noviyanti, Alexandra L Garnham, Diana S Hansen

{"title":"Systems approach identifies monocyte imbalance in symptomatic and asymptomatic P. vivax malaria.","authors":"Stephanie I Studniberg, Mariam Bafit, Lisa J Ioannidis, Matthew J Worley, Leily Trianty, Retno A S Utami, Agatha M Puspitasari, Dwi Apriyanti, Farah N Coutrier, Jeanne R Poespoprodjo, Enny Kenangalem, Benediktus Andries, Pak Prayoga, Ric N Price, Rintis Noviyanti, Alexandra L Garnham, Diana S Hansen","doi":"10.1038/s44320-025-00135-z","DOIUrl":"10.1038/s44320-025-00135-z","url":null,"abstract":"Although asymptomatic malaria was historically perceived as innocuous, emerging evidence revealed an immunosuppressive signature induced by asymptomatic Plasmodium falciparum infections. To examine if a similar process occurs in Plasmodium vivax malaria, we pursued a systems approach, integrating transcriptional profiling together with previously reported and novel mass cytometry phenotypes from individuals with symptomatic and asymptomatic P. vivax malaria. Symptomatic P. vivax malaria featured upregulation of anti-inflammatory pathways and checkpoint receptors. A profound downregulation of transcripts with roles in monocyte function was observed in symptomatic P. vivax malaria. This reduction in monocyte transcriptional activity was accompanied by a significant depletion of CCR2+CXCR4+ classical monocytes in symptomatic individuals. Despite allowing transcriptional profiles supporting T-cell differentiation, dysregulation of genes associated with monocyte activation and the inflammasome was also evident in individuals carrying P. vivax asymptomatic infections. Our results identify monocyte dysregulation as a key feature of the response to P. vivax malaria and support the concept that asymptomatic infection is not innocuous and might not support all immune processes required to eliminate parasitemia or efficiently respond to vaccination.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883230","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

Unique trajectory of gene family evolution from genomic analysis of nearly all known species in an ancient yeast lineage. 独特的基因家族进化轨迹从基因组分析几乎所有已知物种在一个古老的酵母谱系。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-05-27 DOI: 10.1038/s44320-025-00118-0

Bo Feng, Yonglin Li, Biyang Xu, Hongyue Liu, Jacob L Steenwyk, Kyle T David, Xiaolin Tian, Carla Gonçalves, Dana A Opulente, Abigail L LaBella, Marie-Claire Harrison, John F Wolters, Shengyuan Shao, Zhaohao Chen, Kaitlin J Fisher, Marizeth Groenewald, Chris Todd Hittinger, Xing-Xing Shen, Shengying Li, Antonis Rokas, Xiaofan Zhou, Yuanning Li

{"title":"Unique trajectory of gene family evolution from genomic analysis of nearly all known species in an ancient yeast lineage.","authors":"Bo Feng, Yonglin Li, Biyang Xu, Hongyue Liu, Jacob L Steenwyk, Kyle T David, Xiaolin Tian, Carla Gonçalves, Dana A Opulente, Abigail L LaBella, Marie-Claire Harrison, John F Wolters, Shengyuan Shao, Zhaohao Chen, Kaitlin J Fisher, Marizeth Groenewald, Chris Todd Hittinger, Xing-Xing Shen, Shengying Li, Antonis Rokas, Xiaofan Zhou, Yuanning Li","doi":"10.1038/s44320-025-00118-0","DOIUrl":"10.1038/s44320-025-00118-0","url":null,"abstract":"Gene gains and losses are a major driver of genome evolution; their precise characterization can provide insights into the origin and diversification of major lineages. Here, we examined gene family evolution of 1154 genomes from nearly all known species in the medically and technologically important yeast subphylum Saccharomycotina. We found that yeast gene family evolution differs from that of plants, animals, and filamentous ascomycetes, and is characterized by smaller overall gene numbers yet larger gene family sizes for a given gene number. Faster-evolving lineages (FELs) in yeasts experienced significantly higher rates of gene losses-commensurate with a narrowing of metabolic niche breadth-but higher speciation rates than their slower-evolving sister lineages (SELs). Gene families most often lost are those involved in mRNA splicing, carbohydrate metabolism, and cell division and are likely associated with intron loss, metabolic breadth, and non-canonical cell cycle processes. Our results highlight the significant role of gene family contractions in the evolution of yeast metabolism, genome function, and speciation, and suggest that gene family evolutionary trajectories have differed markedly across major eukaryotic lineages.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1066-1089"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160176","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

Signalomics for molecular tumor boards and precision oncology of breast and gynecological cancers. 信号组学用于乳腺癌和妇科肿瘤的分子肿瘤板和精确肿瘤学。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-06-09 DOI: 10.1038/s44320-025-00125-1

Tatiana V Denisenko, Anna E Ivanova, Alexey Koval, Denis N Silachev, Lee Jia, Gennadiy T Sukhikh, Vladimir L Katanaev

{"title":"Signalomics for molecular tumor boards and precision oncology of breast and gynecological cancers.","authors":"Tatiana V Denisenko, Anna E Ivanova, Alexey Koval, Denis N Silachev, Lee Jia, Gennadiy T Sukhikh, Vladimir L Katanaev","doi":"10.1038/s44320-025-00125-1","DOIUrl":"10.1038/s44320-025-00125-1","url":null,"abstract":"Precision oncology led to the establishment and widespread application of molecular tumor boards (MTBs)-multidisciplinary units combining molecular and clinical assessment of individual cancer cases for swift selection of personalized treatments. Whole-exome or gene panel sequencing, combined with transcriptomic, immunohistochemical, and other molecular analyses, often permits dissection of molecular drivers of a tumor and identification of its potential targetable vulnerabilities, instructing clinical oncologists on sometimes unconventional treatment options. However, cancer drivers are often unleashed mutation-independently, especially in breast and gynecological cancers, and deleterious mutations are not always pathogenic. To complement the MTB arsenal, we chart here the molecular toolset we call Signalomics that permits fast and robust assessment of a panel of oncogenic signaling pathways in fresh tumor samples. Using transcriptional reporters introduced in primary tumor cells, this approach identifies the pathways overactivated in a given tumor and validates their sensitivity to targeted therapies, providing actionable insights for personalized treatment strategies. Integration of Signalomics into MTB workflows bridges the gap between molecular profiling and functional pathway analysis, refining clinical treatment decisions and advancing precision oncology.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"952-959"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258611","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

Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells. 途径代谢物比率揭示了增殖细胞子集中独特的谷氨酰胺代谢。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-06-05 DOI: 10.1038/s44320-025-00099-0

Nancy T Santiappillai, Yue Cao, Mariam F Hakeem-Sanni, Jean Yang, Lake-Ee Quek, Andrew J Hoy

{"title":"Pathway metabolite ratios reveal distinctive glutamine metabolism in a subset of proliferating cells.","authors":"Nancy T Santiappillai, Yue Cao, Mariam F Hakeem-Sanni, Jean Yang, Lake-Ee Quek, Andrew J Hoy","doi":"10.1038/s44320-025-00099-0","DOIUrl":"10.1038/s44320-025-00099-0","url":null,"abstract":"Large-scale metabolomic analyses of pan-cancer cell line panels have provided significant insights into the relationships between metabolism and cancer cell biology. Here, we took a pathway-centric approach by transforming targeted metabolomic data into ratios to study associations between reactant and product metabolites in a panel of cancer and non-cancer cell lines. We identified five clusters of cells from various tissue origins. Of these, cells in Cluster 4 had high ratios of TCA cycle metabolites relative to pyruvate, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios. This was due to more glutamine cataplerotic efflux and not glycolysis in cells of Cluster 4. In silico analyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of glutamine metabolism and OXPHOS than cells in Cluster 3. Our results highlight the potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"983-1003"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234582","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

Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion. 控制b细胞群扩增的BCR和CD40信号整合中的协同和拮抗作用。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-06-05 DOI: 10.1038/s44320-025-00124-2

Helen Huang, Haripriya Vaidehi Narayanan, Mark Yankai Xiang, Vaibhava Kesarwani, Alexander Hoffmann

{"title":"Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion.","authors":"Helen Huang, Haripriya Vaidehi Narayanan, Mark Yankai Xiang, Vaibhava Kesarwani, Alexander Hoffmann","doi":"10.1038/s44320-025-00124-2","DOIUrl":"10.1038/s44320-025-00124-2","url":null,"abstract":"In response to infection or vaccination, lymph nodes must select antigen-reactive B-cells while eliminating auto-reactive B-cells. B-cells are instructed via B-cell receptor (BCR), which binds antigen, and CD40 receptor by antigen-recognizing T-cells. How BCR and CD40 signaling are integrated quantitatively to jointly determine B-cell fate decisions remains unclear. Here, we developed a differential-equations-based model of BCR and CD40 signaling networks activating NFκB. The model recapitulates NFκB dynamics upon BCR and CD40 stimulation, and when linked to established cell decision models of cell cycle and survival control, the resulting cell population dynamics. However, upon costimulation, NFκB dynamics were correctly predicted but the predicted potentiated population expansion was not observed experimentally. We found that this discrepancy was due to BCR-induced caspase activity that may trigger apoptosis in founder cells, unless timely NFκB-induced survival gene expression protects them. Iterative model predictions and sequential co-stimulation experiments revealed how complex non-monotonic integration of BCR and CD40 signals controls positive and negative selection of B-cells. Our work suggests a temporal proof-reading mechanism for regulating the stringency of B-cell selection during antibody responses.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1119-1146"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234583","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

From microbes to molecules: unveiling host-microbe interactions with spatial metabolomics. 从微生物到分子：揭示宿主-微生物与空间代谢组学的相互作用。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-06-24 DOI: 10.1038/s44320-025-00129-x

Malin Stüwe, Lars-Erik Petersen, Manuel Liebeke

引用次数: 0

PerturbNet predicts single-cell responses to unseen chemical and genetic perturbations. 摄动网预测单细胞对看不见的化学和遗传扰动的反应。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-07-10 DOI: 10.1038/s44320-025-00131-3

Hengshi Yu, Weizhou Qian, Yuxuan Song, Joshua D Welch

{"title":"PerturbNet predicts single-cell responses to unseen chemical and genetic perturbations.","authors":"Hengshi Yu, Weizhou Qian, Yuxuan Song, Joshua D Welch","doi":"10.1038/s44320-025-00131-3","DOIUrl":"10.1038/s44320-025-00131-3","url":null,"abstract":"Chemical and genetic perturbations, such as those induced by small molecules and CRISPR, effect complex changes in the molecular states of cells. Despite advances in high-throughput single-cell perturbation screening technology, the space of possible perturbations is far too large to measure exhaustively. Here, we introduce PerturbNet, a flexible deep generative model designed to predict the distribution of cell states induced by unseen chemical or genetic perturbations. PerturbNet accurately predicts gene expression changes in response to unseen small molecules based on their chemical structures while also accounting for key covariates such as dosage and cell type. Moreover, PerturbNet accurately predicts the distribution of single-cell gene expression states following CRISPR activation or CRISPR interference by leveraging gene functional annotations. Our approach significantly outperforms previous methods, particularly for predicting the effects of perturbing completely unseen genes. Finally, we demonstrate for the first time that amino acid sequence embeddings can be used to predict gene expression changes induced by missense mutations. We use PerturbNet to predict the effects of all point mutations in GATA1 and nominate variants that significantly impact the cell state distribution of human hematopoietic stem cells. Using a crystal structure of GATA1 bound to DNA, we validate that these large-effect variants occur in the core DNA-contact region of GATA1 and tend to involve large changes in amino acid side-chain volume.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"960-982"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608888","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

Exogenous prion-like proteins and their potential to trigger cognitive dysfunction. 外源性朊病毒样蛋白及其引发认知功能障碍的可能性。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-05-27 DOI: 10.1038/s44320-025-00114-4

Jofre Seira Curto, Adan Dominguez Martinez, Genis Perez Collell, Estrella Barniol Simon, Marina Romero Ruiz, Berta Franco Bordés, Paula Sotillo Sotillo, Sandra Villegas Hernandez, Maria Rosario Fernandez, Natalia Sanchez de Groot

{"title":"Exogenous prion-like proteins and their potential to trigger cognitive dysfunction.","authors":"Jofre Seira Curto, Adan Dominguez Martinez, Genis Perez Collell, Estrella Barniol Simon, Marina Romero Ruiz, Berta Franco Bordés, Paula Sotillo Sotillo, Sandra Villegas Hernandez, Maria Rosario Fernandez, Natalia Sanchez de Groot","doi":"10.1038/s44320-025-00114-4","DOIUrl":"10.1038/s44320-025-00114-4","url":null,"abstract":"The gut is exposed to a wide range of proteins, including ingested proteins and those produced by the resident microbiota. While ingested prion-like proteins can propagate across species, their implications for disease development remain largely unknown. Here, we apply a multidisciplinary approach to examine the relationship between the biophysical properties of exogenous prion-like proteins and the phenotypic consequences of ingesting them. Through computational analysis of gut bacterial proteins, we identified an enrichment of prion-like sequences in Helicobacter pylori. Based on these findings, we rationally designed a set of synthetic prion-like sequences that form amyloid fibrils, interfere with amyloid-beta-peptide aggregation, and trigger prion propagation when introduced in the yeast Sup35 model. When C. elegans were fed bacteria expressing these prion-like proteins, they lost associative memory and exhibited increased lipid oxidation. These data suggest a link between memory impairment, the conformational state of aggregates, and oxidative stress. Overall, this work supports gut microbiota as a reservoir of exogenous prion-like sequences, especially H. pylori, and the gut as an entry point for molecules capable of triggering cognitive dysfunction.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1004-1029"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160032","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

Proteomic compensation by paralogs preserves protein interaction networks after gene loss in cancer. 类似物的蛋白质组补偿保留了癌症中基因丢失后的蛋白质相互作用网络。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-08-01 Epub Date: 2025-05-28 DOI: 10.1038/s44320-025-00122-4

Anjan Venkatesh, Niall Quinn, Swathi Ramachandra Upadhya, Barbara De Kegel, Alfonso Bolado Carrancio, Thomas Lefeivre, Olivier Dennler, Kieran Wynne, Alexander von Kriegsheim, Colm J Ryan

{"title":"Proteomic compensation by paralogs preserves protein interaction networks after gene loss in cancer.","authors":"Anjan Venkatesh, Niall Quinn, Swathi Ramachandra Upadhya, Barbara De Kegel, Alfonso Bolado Carrancio, Thomas Lefeivre, Olivier Dennler, Kieran Wynne, Alexander von Kriegsheim, Colm J Ryan","doi":"10.1038/s44320-025-00122-4","DOIUrl":"10.1038/s44320-025-00122-4","url":null,"abstract":"Proteins operate within dense interconnected networks, with interactions necessary both for stabilising proteins and enabling them to execute their molecular functions. Remarkably, protein-protein interaction networks operating within tumour cells continue to function despite widespread genetic perturbations. Previous work has demonstrated that tumour cells tolerate perturbations of paralogs better than perturbations of singleton genes, but the underlying mechanisms remain poorly understood. Here, we systematically profile the proteomic response of tumours and cell lines to gene loss. We find many examples of proteomic compensation, where loss of one gene causes increased abundance of a paralog, and collateral loss, where gene loss causes reduced paralog abundance. Compensation is enriched among paralog pairs that are central in the protein-protein interaction network and whose interaction partners perform essential functions. Compensation is also significantly more likely to be observed between synthetic lethal pairs. Our results support a model whereby loss of one gene results in increased protein abundance of its paralog, stabilising the protein-protein interaction network. Consequently, tumour cells may become dependent on the paralog for survival, creating potentially targetable vulnerabilities.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1090-1118"},"PeriodicalIF":7.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12322171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174048","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