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

Necrotizing soft tissue infections (NSTIs) kill 25-35% of patients despite antibiotic treatment. Two causes of NSTIs are Streptococcus pyogenes and Clostridium perfringens. They produce the cholesterol-dependent cytolysins (CDCs) streptolysin O (SLO) and perfringolysin O (PFO). CDCs damage cell membranes. Cells resist this damage using Ca(2+)-dependent repair pathways, including MEK-dependent microvesicle shedding, dysferlin-mediated patch repair, and annexin-mediated membrane clogging. While 70% of this repair is MEK-dependent, the upstream regulators are unclear. Here, we show that the Rac GEF Vav2, triggers MLK3-MEK-dependent repair. Inhibiting or knocking down Vav2 sensitized multiple cell types to CDCs, whereas blocking other Rac GEFs did not. Vav2 accounted for ~90% of Ca(2+)-dependent membrane repair. MEK activation rescued repair in Vav2-inhibited cells. Vav2 inhibition failed to exacerbate damage in cells lacking dysferlin or annexins, suggesting Vav2 coordinates multiple repair pathways. Thus, Vav2 controls multiple Ca(2+)-activated repair pathways that protect cells from CDCs produced during NSTIs.