PLoS Biology最新文献_第7页

Monovalent cations differentially regulate the activity of eukaryotic fluoride channels and impact fluoride resistance. 一价阳离子对真核生物氟离子通道活性的差异调控和对氟离子抗性的影响。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3004008

Chia-Yu Kang, Sahar Heidari, Sabrina Kolb, Minjun An, Melanie D Ohi, Hedieh Torabifard, Randy B Stockbridge

{"title":"Monovalent cations differentially regulate the activity of eukaryotic fluoride channels and impact fluoride resistance.","authors":"Chia-Yu Kang, Sahar Heidari, Sabrina Kolb, Minjun An, Melanie D Ohi, Hedieh Torabifard, Randy B Stockbridge","doi":"10.1371/journal.pbio.3004008","DOIUrl":"10.1371/journal.pbio.3004008","url":null,"abstract":"Fluoride is an environmentally prevalent inhibitor of fungi, plants, and other eukaryotes. The fluoride exporter (FEX) is the major resistance mechanism that prevents intracellular fluoride accumulation in eukaryotes. FEX activity is sodium-dependent, but the mechanism for Na+ activation and the impact of other cations on FEX function remain poorly understood. Here, we show that sodium and lithium have different effects on channel activity. We leverage these differences to understand how monovalent cations regulate FEX. Functional assays in a reconstituted system show that lithium acts as a competitive antagonist of channel activation by competing with sodium for the central cation binding site. We further demonstrate that lithium markedly reduces fluoride tolerance of yeast. A cryo-EM structure of Candida albicans FEX with Li+, together with molecular dynamics (MD) simulations, reveals that differences in the preferred coordination sphere underlie the cation dependence of FEX activity. Whereas sodium binding supports a dynamic structure with a broader pore radius, lithium coordination favors a more rigid conformation that is more compact in the channel's vestibule. These changes perturb the tilt angle of a pore lining helix, and alter the rotamer of a key phenylalanine in the pore, which together constrict the permeation pathway. In addition to providing general insight into the mechanism of fluoride channel regulation by monovalent cations, these results identify lithium as a previously unknown environmental antagonist of eukaryotic fluoride export and tie cellular fluoride stress tolerance to the abundance of additional ions in the cellular milieu.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3004008"},"PeriodicalIF":7.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018436","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

Myelin sheath lengths in the central nervous system scale to axon diameter via oligodendroglial Piezo1. 中枢神经系统髓鞘长度通过少突胶质Piezo1与轴突直径成比例。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3003992

Amanda R Young, Ashley Galfano, Jacob Reyngoudt, Ryan W Lewis, Martha Cash, Beckam Polis, Myah Zalusky, Avipsha Datta, Marie E Bechler

{"title":"Myelin sheath lengths in the central nervous system scale to axon diameter via oligodendroglial Piezo1.","authors":"Amanda R Young, Ashley Galfano, Jacob Reyngoudt, Ryan W Lewis, Martha Cash, Beckam Polis, Myah Zalusky, Avipsha Datta, Marie E Bechler","doi":"10.1371/journal.pbio.3003992","DOIUrl":"10.1371/journal.pbio.3003992","url":null,"abstract":"Myelin sheath lengths vary by an order of magnitude in the central nervous system (CNS) and tune the timing of neuronal signaling. Thus, variation in myelin sheath length has been proposed to coordinate the timing of neuronal signaling to ultimately impact behavior. The mechanisms to establish myelin sheath length are unknown. For decades, reports have documented that in vivo myelin sheath size scales with the diameter of the ensheathed axon. We previously demonstrated diameter is sufficient to instruct myelin sheath lengths formed by rat oligodendrocytes using a synthetic axon culture system. The mechanisms of oligodendrocyte diameter-sensing and its translation into sheath elongation are still unknown. Here, we demonstrate that diameter-sensing and sheath length is locally regulated: each individual myelin sheath responds to the underlying fiber diameter. We uncover a novel mechanism for scaling myelin sheath length to fiber diameter, through mechanosensitive ion channel Piezo1. In mice in vivo, Piezo1 impacts the elongation of myelin sheaths on large diameter axons, recapitulating our in vitro results. Yet, surprisingly, there is no impact on myelin thickness with conditional Piezo1 loss. We propose Piezo1 provides a mechanism to establish hard-wired myelin sheath patterns, where oligodendrocytes transduce axon diameter into generating myelin segments with vastly different lengths.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3003992"},"PeriodicalIF":7.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13592707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018442","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

The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system. 秀丽隐杆线虫具有阳离子两亲性药物（CAD）防御系统。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3004006

Levon Tokmakjian, Duhyun Han, Kateryna Sihuta, Aanchal Aggarwal, Somayeh Pirhadi, Yao Wang, Andrew R Burns, Brittany Cooke, Siyue Ren, Marios Gavrielatos, Jiabao Liu, Henry M Krause, Carolyn L Cummins, Justin Nodwell, David R Koes, Peter J Roy

{"title":"The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system.","authors":"Levon Tokmakjian, Duhyun Han, Kateryna Sihuta, Aanchal Aggarwal, Somayeh Pirhadi, Yao Wang, Andrew R Burns, Brittany Cooke, Siyue Ren, Marios Gavrielatos, Jiabao Liu, Henry M Krause, Carolyn L Cummins, Justin Nodwell, David R Koes, Peter J Roy","doi":"10.1371/journal.pbio.3004006","DOIUrl":"10.1371/journal.pbio.3004006","url":null,"abstract":"Cationic Amphiphilic Drugs (CADs) severely disrupt lysosomal function, which leads to a cellular pathology in humans characterized by excess phospholipids called phospholipidosis. Through a forward genetic screen and mining of published datasets, we discovered that CADs induce the expression of the CYP-35B family of cytochrome P450s and the PGP-13 p-glycoprotein pump via the nuclear receptors NHR-70 and NHR-107 in the nematode C. elegans. A pgp-13 fluorescent reporter revealed hundreds of human drugs that up-regulate the CAD defense system in vivo. Chemoinformatic analyses indicate that the pgp-13 reporter may be useful in identifying CADs that have pathogenic potential in humans. Mutant analyses coupled to metabolomics and structural modeling show that the CYP-35Bs are necessary and sufficient for CAD metabolism, and that CYP-35B2 D311 is key in mediating electrostatic interactions with the positively charged CADs. We also show that CAD metabolites are effluxed via PGP-13 acting partially redundantly with PGP-14 and that an intact defense system is necessary to resist CAD-induced pathology. Finally, we demonstrate that bacteria that likely cohabitate with C. elegans in nature trigger the CAD defense system, providing a plausible explanation for why a pathway that protects against anthropogenic small molecules exists in nematodes.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3004006"},"PeriodicalIF":7.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018513","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

AlloPool is a deep learning framework that infers protein allostery from molecular dynamics simulations. AlloPool是一个深度学习框架，可以从分子动力学模拟中推断蛋白质变构。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3004002

Matthieu Marfoglia, Miguel A Pedraza-Joya, Lucas Guirardel, Aisima Chatzi Souleiman, Patrick Barth

{"title":"AlloPool is a deep learning framework that infers protein allostery from molecular dynamics simulations.","authors":"Matthieu Marfoglia, Miguel A Pedraza-Joya, Lucas Guirardel, Aisima Chatzi Souleiman, Patrick Barth","doi":"10.1371/journal.pbio.3004002","DOIUrl":"10.1371/journal.pbio.3004002","url":null,"abstract":"Recent advances in artificial intelligence have transformed protein structure prediction and design. However, protein function is governed not only by static structures but also by the conformational dynamics that allow proteins to access distinct functional states. Predicting these dynamic transitions, central to many biological processes, remains challenging due to the scarcity of high-resolution experimental data, which limits the training of machine-learning models for dynamic and energetic property prediction. Here, we present AlloPool, a graph neural network (GNN)-based framework that interprets molecular dynamics simulations by iteratively pruning residue-residue interactions to uncover minimal, time-resolved interaction networks that govern protein conformational dynamics and structural responses to chemical or mechanical perturbations, collectively known as allostery. By integrating temporal attention with graph aggregation, AlloPool learns evolving interaction graphs from equilibrium and non-equilibrium molecular dynamics simulations, enabling accurate reconstruction of dynamic trajectories and the interaction networks that drive conformational transitions. Validated across diverse dynamic protein systems, including binding domains, mechanosensors, signaling receptors, and enzymes, AlloPool maps allosteric communication pathways, predicts the effects of ligand binding, mechanical forces, and mutations, discovers transient dynamic states and outperforms existing machine-learning approaches in dynamic trajectory reconstruction. This advance provides a general framework for interpreting protein dynamics with broad implications for drug discovery, synthetic biology, and protein engineering.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3004002"},"PeriodicalIF":7.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13592721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018483","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

MucD regulates alginate biosynthesis through the proteolytic control of AlgX and AlgK in Pseudomonas aeruginosa. MucD通过控制铜绿假单胞菌中AlgX和AlgK的蛋白水解来调节海藻酸盐的生物合成。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3003985

Yujun Jiang, Xin-Fu Yan, Rya Ero, Chao Wang, Kanaga Sabapathy, Yong-Gui Gao

{"title":"MucD regulates alginate biosynthesis through the proteolytic control of AlgX and AlgK in Pseudomonas aeruginosa.","authors":"Yujun Jiang, Xin-Fu Yan, Rya Ero, Chao Wang, Kanaga Sabapathy, Yong-Gui Gao","doi":"10.1371/journal.pbio.3003985","DOIUrl":"10.1371/journal.pbio.3003985","url":null,"abstract":"Pseudomonas aeruginosa is an opportunistic human pathogen capable of infecting a wide range of tissues and organs. Its persistence during chronic infection is strongly associated with biofilm formation, which depends on extracellular polysaccharides such as alginate. The HtrA-like periplasmic serine protease MucD is a key regulator of bacterial virulence, stress response, and alginate production, yet its molecular mechanism has remained largely unclear. Here, we discovered the alginate acetylation and export proteins AlgX and AlgK as MucD substrates, and characterized their degradation by mass spectrometry and bioinformatic analysis. We further determined the cryo-EM structure of MucD bound to an AlgK-derived substrate peptide, offering atomic insights into MucD oligomerization assembly, substrate recognition, and specificity. Together with structure-guided mutagenesis and biochemical assays, our results revealed that MucD proteolytic activity is governed by an equilibrium between a resting 12-mer and an active trimer. Crucially, we demonstrate that MucD represses alginate biosynthesis post-translationally, in addition to its previously implicated role in transcriptional regulation. These findings define a distinct activation mechanism and regulatory function for MucD and provide new insight into bacterial HtrA-like serine proteases.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3003985"},"PeriodicalIF":7.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13608001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018473","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

Regeneration programs buffer genetic defects in animal development. 再生计划可以缓冲动物发育过程中的遗传缺陷。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3004011

Kazunori Ando, Sushant Bangru, John Welsby, John D Thompson, Kenneth D Poss

{"title":"Regeneration programs buffer genetic defects in animal development.","authors":"Kazunori Ando, Sushant Bangru, John Welsby, John D Thompson, Kenneth D Poss","doi":"10.1371/journal.pbio.3004011","DOIUrl":"10.1371/journal.pbio.3004011","url":null,"abstract":"Regeneration programs enable animals to restore damaged or lost tissues, and the range of stimuli for these programs is incompletely understood. Here, we used zebrafish, a vertebrate species with exceptional regenerative capacity, to identify chemically induced mutations that alter regeneration-associated gene activation. Transgenic zebrafish with a permissive promoter and EGFP cassette inserted in the vicinity of the pro-regenerative factor gene fgf20a were mutagenized, and larvae homozygous for ENU-induced mutations were assessed for disruptions in fgf20a-directed reporter gene expression following fin fold amputation. One line was identified with heritable, elevated fgf20a:EGFP presence in the absence of experimental injury, localized to regions of fin fold tissue undergoing degeneration. Whole-genome sequencing identified a mutation within exon 72 of the fraser syndrome 1 (fras1) gene, mutated in patients with inherited skin disease. fras1 mutant larvae spontaneously displayed broader signatures of regeneration, and zebrafish crispants for homologs of other genes mutated in human developmental diseases also displayed regeneration-associated gene expression in regions of dysmorphology. Tempering Fgf signaling by transgenic expression of a dominant-negative Fgf receptor in fras1 mutants exacerbated the disease phenotype. Our findings provide evidence that regeneration programs are harnessed in response to developmental defects caused by genetic mutations, potentially buffering deleterious phenotypes.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3004011"},"PeriodicalIF":7.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018457","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

The kinetoplastid-specific transcription factor mtTF1 is essential for mitochondrial gene expression and maxicircle replication in Trypanosoma brucei. 胞浆体特异性转录因子mtTF1对布鲁氏锥虫线粒体基因表达和最大环复制至关重要。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3003945

Bianca Manuela Berger, Enrico Santini, Himaja Manjunatha, Lea Trost, Markus Gerber, Hauke S Hillen, Torsten Ochsenreiter

引用次数: 0

Gene flow drives periods of both evolutionary stasis and change in a wild bird population. 在野生鸟类种群中，基因流动驱动着进化停滞期和变化期。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-21 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3004004

Simon R Evans, Henri Bouwmeester, Arie J van Noordwijk, Marcel E Visser, Erik Postma

{"title":"Gene flow drives periods of both evolutionary stasis and change in a wild bird population.","authors":"Simon R Evans, Henri Bouwmeester, Arie J van Noordwijk, Marcel E Visser, Erik Postma","doi":"10.1371/journal.pbio.3004004","DOIUrl":"10.1371/journal.pbio.3004004","url":null,"abstract":"The struggle to explain the absence of evolutionary change in heritable, fitness-related traits of free-living populations has become emblematic of our ignorance of the evolutionary process in the wild. Yet while this 'paradox of stasis' has been the subject of much discussion, it is primarily identified a posteriori and rarely subject to direct quantification. We examined the evolution of clutch size in neighbouring populations of great tits (Parus major) before, during and after an experimental evolutionary perturbation. Interannual genetic changes in clutch size were directionally consistent with selection (refuting absolute stasis) but were smaller than predicted by adaptive evolutionary models (supporting relative stasis). Yet accounting for the contribution of post-selective immigration (i.e., explicitly recognising the distinction between adaptation and evolution) greatly improved our forecast accuracy and this tendency toward overprediction. Indeed, attributing interannual genetic change to its contributing demographic processes revealed immigration to be key to explaining periods of both evolutionary stasis and change, with its evolutionary impact varying across time and space in a manner analogous to the dynamism of natural selection. Our multi-decadal study of clutch size evolution thus shows that recognising the impact of gene flow is crucial to explaining contemporary evolutionary change and stasis of a key determinant of life history.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3004004"},"PeriodicalIF":7.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018489","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

Regional signaling controls stem cell-mediated regeneration in an invertebrate chordate. 区域信号控制无脊椎脊索动物干细胞介导的再生。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-18 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3004000

Tal Gordon, Tom Levy, Chester Jiamu Yu, Benyamin Rosental, Lauren Lubeck, Lucia Manni, Irving L Weissman, Ayelet Voskoboynik

{"title":"Regional signaling controls stem cell-mediated regeneration in an invertebrate chordate.","authors":"Tal Gordon, Tom Levy, Chester Jiamu Yu, Benyamin Rosental, Lauren Lubeck, Lucia Manni, Irving L Weissman, Ayelet Voskoboynik","doi":"10.1371/journal.pbio.3004000","DOIUrl":"10.1371/journal.pbio.3004000","url":null,"abstract":"Many tissues harbor quiescent stem cells that activate after injury, yet how local signals regulate this transition is not well understood. The solitary ascidian Ciona robusta provides a unique model, as bottom body fragments regenerate while upper fragments fail to do so. By comparing these regenerative and non-regenerative contexts, we reveal striking differences in transcriptional dynamics and signaling environments. Combining flow cytometry, scRNA-seq, transplantation, and fate mapping, we identified a candidate stem cell population with robust proliferative and differentiation potential following transplantation. However, regenerative capacity does not simply reflect stem cell abundance, but instead depends on region-specific signaling cues. Local expression of metabolic, immune and differentiation-related factors further underscores the importance of spatially distinct environments in shaping outcomes. Our findings show how a shared injury response is associated with divergent regenerative outcomes, highlighting principles that may inform strategies to enhance tissue repair in other systems.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3004000"},"PeriodicalIF":7.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002716","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

Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation. 胶原I通过氨基酸输入和mTORC1/S6激活促进癌细胞存活。

IF 7.2 1区生物学

PLoS Biology Pub Date : 2026-09-18 eCollection Date: 2026-09-01 DOI: 10.1371/journal.pbio.3003555

Mona Nazemi, Bian Yanes, Eric Vancauwenberghe, Ifeoluwa Oyelade, Heather Walker, Elena Rainero

{"title":"Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.","authors":"Mona Nazemi, Bian Yanes, Eric Vancauwenberghe, Ifeoluwa Oyelade, Heather Walker, Elena Rainero","doi":"10.1371/journal.pbio.3003555","DOIUrl":"10.1371/journal.pbio.3003555","url":null,"abstract":"Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the LAT1-4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1-4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"24 9","pages":"e3003555"},"PeriodicalIF":7.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13614659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002632","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