RNA translational regulation by CPEB4 orchestrates platelet function and pathophysiology

RNA translational regulation by CPEB4 orchestrates platelet function and pathophysiology | 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 RNA translational regulation by CPEB4 orchestrates platelet function and pathophysiology Pilar Navarro, Begoña Hurtado, Joan Gibert, Núria Vázquez-Bellón, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5588659/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 Platelets are highly specialized anucleate cells that play crucial roles in haemostasis, inflammation and disease. Recent data suggest that mRNA translational control is the primary mechanism of gene regulation in platelets. This study unveils a novel pathway to control mRNA translation and protein expression in platelets via the mRNA binding protein CPEB4. We found high CPEB4 expression levels in human and mouse platelets, colocalizing with cytoskeletal proteins. In vivo loss-of-function studies, using the megakaryocytic lineage-specific Pf4-Cre transgenic mice crossed with a strain containing loxP-flanked CPEB4 (Pf4+:Cpeb4–/– mice), revealed a significant reduction of platelet activation and aggregation. These effects were specific to mature platelets, as CPEB4 deficiency did not significantly impact megakaryocytopoiesis. Functional assays, including tail bleeding and collagen-induced embolism, demonstrated impaired coagulation in Pf4+:Cpeb4–/– mice compared to controls. Furthermore, proteomics analysis of resting and activated platelets from Pf4–:Cpeb4+/+ and Pf4+:Cpeb4–/– mice identified a molecular signature of proteins and networks regulated by CPEB4, including those involved in haemostasis and platelet clearance. Our study reveals CPEB4-mediated mRNA translational regulation as a novel fine-tuning mechanism for modulating protein synthesis in platelets, with significant functional consequences in both physiological and pathological conditions. Biological sciences/Biochemistry/RNA Health sciences/Cardiology/Cardiovascular biology/Platelets Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTableS1Proteomics.xlsx Dataset S1 SupplementaryTableS2DErestingmouseplateletsCPEprediction.xlsx Dataset S2 SupplementaryTableS3DEactivatedmouseplateletsCPEprediction.xlsx Dataset S3 SupplementaryTableS4GOCPEBtargetsDEKOvsWTresting.xlsx Dataset S4 SupplementaryTableS5GOCPEBtargetsDEKOvsWTactivated.xlsx Dataset S5 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5588659","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":389869693,"identity":"11c88034-8b04-4785-9f09-6efba3125ce1","order_by":0,"name":"Pilar 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Recent data suggest that mRNA translational control is the primary mechanism of gene regulation in platelets. This study unveils a novel pathway to control mRNA translation and protein expression in platelets via the mRNA binding protein CPEB4. We found high CPEB4 expression levels in human and mouse platelets, colocalizing with cytoskeletal proteins. In vivo loss-of-function studies, using the megakaryocytic lineage-specific Pf4-Cre transgenic mice crossed with a strain containing loxP-flanked CPEB4 (Pf4+:Cpeb4–/– mice), revealed a significant reduction of platelet activation and aggregation. These effects were specific to mature platelets, as CPEB4 deficiency did not significantly impact megakaryocytopoiesis. Functional assays, including tail bleeding and collagen-induced embolism, demonstrated impaired coagulation in Pf4+:Cpeb4–/– mice compared to controls. 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