Salmonella SipA mimics a cognate SNARE for host Syntaxin8 to promote fusion with early endosomes

SipA is a major effector of Salmonella, which causes gastroenteritis and enteric fever. Caspase-3 cleaves SipA into two domains: the C-terminal domain regulates actin polymerization, whereas the function of the N terminus is unknown. We show that the cleaved SipA N terminus binds and recruits host Syntaxin8 (Syn8) to Salmonella-containing vacuoles (SCVs). The SipA N terminus contains a SNARE motif with a conserved arginine residue like mammalian R-SNAREs. SipA(R204Q) and SipA(1-435R204Q) do not bind Syn8, demonstrating that SipA mimics a cognate R-SNA RE for Syn8. Consequently, Salmonella lacking SipA or that express the SipA(1-435R204Q) SNARE mutant are unable to recruit Syn8 to SCVs. Finally, we show that SipA mimicking an R-SNA RE recruits Syn8, Syn13, and Syn7 to the SCV and promotes its fusion with early endosomes to potentially arrest its maturation. Our results reveal that SipA functionally substitutes endogenous SNAREs in order to hijack the host trafficking pathway and promote Salmonella survival.