Rewired DEPTOR-mTORC1/2 signaling stabilizes cardiac fibroblast survival and activation

Rewired DEPTOR-mTORC1/2 signaling stabilizes cardiac fibroblast survival and activation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Rewired DEPTOR-mTORC1/2 signaling stabilizes cardiac fibroblast survival and activation Daniel Sanchis, Sandra García-Carpi, Carlos Lana, Aida Beà, Juan Valero, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9081294/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Cardiac fibroblasts (CFs) are resistant to stress-induced death, a property important for tissue repair but also central to pathological fibrosis and heart failure. Comparative transcriptomic and proteomic analyses identified the mTOR-interacting protein DEPTOR as selectively enriched in CFs. Although DEPTOR is widely characterized as an inhibitor of mTORC1 and mTORC2 in tumor and immortalized cells, its role in differentiated somatic cells remains unclear. Here, we show that CFs display a context-dependent DEPTOR-mTOR signaling configuration in which DEPTOR sustains, rather than inhibits, mTOR-dependent outputs. DEPTOR silencing in adult CFs attenuates mTORC1 signaling with branch-specific sensitivity and strongly reduces BCL2, an integrative survival output of mTORC1/2 signaling. This leads to impaired α-smooth muscle actin induction and reduced fibroblast survival under stress, while AKT Ser473 phosphorylation remains comparatively buffered. Pharmacological dissection of the PI3K-mTOR axis supports DEPTOR as a stabilizer of this pro-survival network. Importantly, fibroblast-specific DEPTOR knockdown in vivo limits post-infarction fibrosis and preserves cardiac function. These findings redefine DEPTOR function in a differentiated somatic cell type, revealing a context-dependent mode of mTOR regulation shaping fibroblast behavior during cardiac injury. Biological sciences/Cell biology/Cell signalling Health sciences/Cardiology/Cardiovascular biology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files DEPTORarticleSUPPLINFORMATION.pdf Supplementary information Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9081294","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":604327983,"identity":"283a6bdc-5a7a-4e4e-8034-3092d1119862","order_by":0,"name":"Daniel Sanchis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYDCCAyBUAGayMSQw2DAwHCdKiwFcSxoDw2EQOwG/Fga4FrB6Qlr4jp89eOCDAYM9/+zmZw8e/Dmf2HeYgfHDzx+4tUieyUs4OMOAIXHGnWPmBolttxNnHmZgluzBY4vBgRyDwzwGQIfcyGGTSGy4nbjhMNCFPPi0nH9jcPgP0GHyIC0Jf86BtTD+waflBtAWoPcZN4C1sB0Aa2HGZ4vkjTcGB3sMJBI33kgzk0hsSzaeeZixWVomDbcWvvM5xh9+VNjYy91Ifib544+dbN/x5oMf39jg1gIFEsgcxgaC6kfBKBgFo2AU4AcAbYZXZG7KE4wAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-0047-8533","institution":"Universitat de Lleida, Edifici Biomedicina-I. 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Comparative transcriptomic and proteomic analyses identified the mTOR-interacting protein DEPTOR as selectively enriched in CFs. Although DEPTOR is widely characterized as an inhibitor of mTORC1 and mTORC2 in tumor and immortalized cells, its role in differentiated somatic cells remains unclear. Here, we show that CFs display a context-dependent DEPTOR-mTOR signaling configuration in which DEPTOR sustains, rather than inhibits, mTOR-dependent outputs. DEPTOR silencing in adult CFs attenuates mTORC1 signaling with branch-specific sensitivity and strongly reduces BCL2, an integrative survival output of mTORC1/2 signaling. This leads to impaired α-smooth muscle actin induction and reduced fibroblast survival under stress, while AKT Ser473 phosphorylation remains comparatively buffered. Pharmacological dissection of the PI3K-mTOR axis supports DEPTOR as a stabilizer of this pro-survival network. 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