Vav2 is a master regulator of repair against bacterial pore-forming toxins

Abstract

Abstract

ABSTRACT Despite antibiotic therapy, 25-35% of patients with necrotizing soft tissue infections (NSTIs) die. The etiologic agents for NSTIs include Streptococcus pyogenes and Clostridium perfringens , which secrete the cholesterol-dependent cytolysins (CDCs) streptolysin O and perfringolysin O to disrupt cell membranes. While cells resist this damage by activating Ca 2+ -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 2+ -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 2+ -activated repair pathways that protect cells from CDCs produced during NSTIs. Teaser This one protein accounts for almost all Ca2+-dependent repair by activating at least 3 distinct pathways.