{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T02:07:16Z","timestamp":1778810836237,"version":"3.51.4"},"posted":{"date-parts":[[2025,8,1]]},"group-title":"Cell Biology","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R21AI156225"],"award-info":[{"award-number":["R21AI156225"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["23IPA1053083"],"award-info":[{"award-number":["23IPA1053083"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Despite antibiotic therapy, 25-35% of patients with necrotizing soft tissue infections (NSTIs) die. The etiologic agents for NSTIs include\n                  <jats:italic>Streptococcus pyogenes<\/jats:italic>\n                  and\n                  <jats:italic>Clostridium perfringens<\/jats:italic>\n                  , which secrete the cholesterol-dependent cytolysins (CDCs) streptolysin O and perfringolysin O to disrupt cell membranes. While cells resist this damage by activating Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -dependent repair pathways, including MEK-dependent microvesicle shedding, dysferlin-mediated patch repair, and annexin-mediated membrane clogging, the upstream regulators of these responses have remained elusive. Here, we demonstrated that the Rac GEF Vav2 accounts for almost all of Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -dependent repair against CDCs. Inhibiting or knocking down Vav2 sensitized multiple cell types to CDCs, whereas blocking other Rac GEFs did not. Mechanistically, Vav2 triggered the critical MLK3-MEK-dependent repair pathway. MEK activation rescued repair in Vav2-inhibited cells. Blocking dysferlin or annexins failed to increase damage beyond Vav2 inhibition, suggesting Vav2 coordinates multiple repair pathways. Thus, Vav2 controls multiple Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -activated repair pathways that protect cells from CDCs produced during NSTIs.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Teaser<\/jats:title>\n                  <jats:p>This one protein accounts for almost all Ca2+-dependent repair by activating at least 3 distinct pathways.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.31.668026","type":"posted-content","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T11:50:16Z","timestamp":1754049016000},"source":"Crossref","is-referenced-by-count":0,"title":["Vav2 is a master regulator of repair against bacterial pore-forming toxins"],"prefix":"10.64898","author":[{"given":"Victor Gbenga","family":"Kayejo","sequence":"first","affiliation":[{"name":"Department of Biological Sciences Texas Tech University Lubbock, TX 79409"},{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University College Station, TX 77843"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashlee","family":"Hensley","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Texas Tech University Lubbock, TX 79409"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tejal","family":"Katore","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Texas Tech University Lubbock, TX 79409"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8637-8538","authenticated-orcid":false,"given":"Peter A.","family":"Keyel","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Texas Tech University Lubbock, TX 79409"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051418103553000_2025.07.31.668026v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2013.11.048"},{"key":"2026051418103553000_2025.07.31.668026v2.2","doi-asserted-by":"crossref","unstructured":"Alves S , Pereira JM , Mayer RL , Goncalves ADA , Impens F , Cabanes D , Sousa S (2022) Cells Responding to Closely Related Cholesterol-Dependent Cytolysins Release Extracellular Vesicles with a Common Proteomic Content Including Membrane Repair Proteins. 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