ARHGEF2 Isoform Switching Couples Intestinal Epithelial Barrier Function with Autophagic Response to Pathogens

ARHGEF2 Isoform Switching Couples Intestinal Epithelial Barrier Function with Autophagic Response to Pathogens | 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 Biological Sciences - Article ARHGEF2 Isoform Switching Couples Intestinal Epithelial Barrier Function with Autophagic Response to Pathogens Hans-Christian Reinecker, Shuyuan Chen, Alka Diwaker, Xi Li, Abdulmajeed Salamah, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8252764/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Maintenance of intestinal epithelial integrity is essential for host defence, yet how epithelial junctional scaffolds connect to antimicrobial autophagy remains unclear. Here we show that distinct isoforms of the guanine nucleotide exchange factor GEF-H1 (mouse Arhgef2-207; human ARHGEF2-219) localize to adherens junctions in polarized intestinal epithelial cells through interaction with the adhesion molecule Nectin-3 and the cytoskeletal scaffold Afadin. Conditional deletion of Arhgef2-207 in the intestinal epithelium induces compensatory expression of the shorter Arhgef2-201, leading to loss of barrier integrity, activation of autophagy, and small-intestinal inflammation. In human intestinal organoids, infection with Listeria monocytogenes selectively targets the junction-associated ARHGEF2-219 isoform, triggering an isoform switch to ARHGEF2-201 and induction of autophagy through interaction with STING and LC3. This transition coincides with a loss of Na⁺/K⁺-ATPase and epithelial polarity. Together, these findings identify a pathogen-induced ARHGEF2 isoform switch that links junctional perturbation to autophagy and mucosal immune activation, defining a previously unrecognized pathway by which epithelial cells couple barrier disruption to cell-intrinsic host defence. Biological sciences/Cell biology/Mechanisms of disease Biological sciences/Cell biology/Autophagy/Macroautophagy Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable3.xlsx Table S3 SupplementaryTable1.xlsx Table S1 SupplementaryTableS5.pdf Table S5 SupplementaryTable2.xlsx Table S2 SupplementaryInformation.pdf Supplementary Information SupplementaryTable4.xlsx Table S4 Cite Share Download PDF Status: Under Review 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. 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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-8252764","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":556942059,"identity":"1b2d3d16-b8c9-4860-bde9-0a0f580d2a71","order_by":0,"name":"Hans-Christian 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