Abstract
Mouse caspase-11 and human caspase-4and caspase-5 recognize cytosolic lipopolysaccharide (LPS) to induce pyroptosis by cleaving the pore-forming protein GSDMD1-5. This non-canonical inflammasome defends against Gram-negative bacteria6,7. Shigella flexneri, which causes bacillary dysentery, lives freely within thehost cytosol where these caspases reside. However, the role of caspase-11-mediated pyroptosis in S. flexneri infection is unknown. Here we show that caspase-11 did not protect mice from S. flexneri infection, in contrast to infection with another cytosolic bacterium, Burkholderia thailandensis8. S. flexneri evaded pyroptosis mediated bycaspase-11or caspase4(hereafter referred to as caspase-11/4) using a type III secretion system (T3SS)effector, OspC3. OspC3, but not its paralogues OspC1and2, covalently modified caspase-11/4; although it used the NAD+ donor, this modificationwas not ADP-ribosylation. Biochemical dissections uncovered an ADP-riboxanation modification on Arg314and Arg310 in caspase-4and caspase-11, respectively. The enzymatic activity was shared by OspC1and2, whose ankyrin-repeat domains, unlike that of OspC3, could not recognize caspase-11/4. ADP-riboxanation of the arginine blocked autoprocessing ofcaspase-4/11 as well as their recognition and cleavage of GSDMD. ADP-riboxanation ofcaspase-11 paralysed pyroptosis-mediated defence in Shigella-infected miceand mutation of ospC3 stimulated caspase-11- andGSDMD-dependent anti-Shigella humoral immunity, generating a vaccine-like protective effect. Our study establishes ADP-riboxanation of arginine as a bacterial virulence mechanism that prevents LPS-induced pyroptosis.
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call