Substrates: OspC3 catalyzes the NAD+-dependent ADP-riboxanation modification on Arg314 and Arg310 in human caspase-4 and murine caspase-11, respectively. The enzyme does not perform ADP-ribosylation of the substrate Products: -
deamino-NAD+, biotin-NAD+, epsilon-NAD+ or nicotinamide guanine dinucleotide (NGD+) allow modifications that preserve the mass difference between the cognate analogue and NAD+ confirming the transfer of ADP-ribosylarginine (ADPR) to caspase-4 with Nam being the leaving group
mutation of ospC3 stimulates caspase-11- and GSDMD-dependent anti-Shigella humoral immunity, generating a vaccine-like protective effect. Wild-type mice survive Shigella flexneri DELTAospC3 infection, and this effect is reversed by complementation with wild-type OspC3 but not the E192A/H328A mutant. Accordingly, mice infected with DELTAospC3 alone or DELTAospC3 expressing OspC3 E192A/H328A have lower bacterial burdens than mice infected with the wild-type OspC3-expressing strain. Random mutagenesis identified Phe141, Phe186, Glu192, Glu326 and His328 in OspC3 as essential for ADP-riboxanating caspase-4/11 and blocking pyroptosis. Another D177A mutation supports ADP-ribosylation but blocks subsequent deamination. Although OspC3(D177A)-modified caspase-4 is sensitive to ADP-ribosylarginine hydrolase (ADPRH), wild-type OspC3-catalysed ADP-riboxanation resists demodification by ADPRH and other known host ADP-ribosylhydrolases. Thus, hijacking of caspase-4/11 by ADP-riboxanation is more advantageous to bacterial virulence
Shigella lacking the ospC3 gene augment necrotic epithelial cell death. Direct interaction between OspC3 and caspase-4. OspC3 interacts with the Casp4-p19 subunit. Casp4 knockdown restores DELTAospC3-induced cell death
Shigella uses OspC3 to modify caspase-11/4 and thereby thwart the inflammasome/pyroptosis-mediated defence. The ADP-riboxanation of arginine is a bacterial virulence mechanism that prevents LPS-induced pyroptosis. OspC3 catalyses arginine ADP-riboxanation, the activity is shared by the OspC family in bacteria
caspase-mediated inflammatory cell death acts as an intrinsic defense mechanism against infection. Bacterial pathogens deploy countermeasures against inflammatory cell death
Shigella flexneri evades pyroptosis in host cells mediated by caspase-11 or caspase 4 using a type III secretion system (T3SS) effector, OspC3. OspC3, but not its paralogues OspC1 and OspC2, covalently modifies caspase-11 and caspase-4. OspC3 catalyzes an NAD+-dependent ADP-riboxanation modification on Arg314 and Arg310 in human caspase-4 and murine caspase-11, respectively. ADP-riboxanation of the arginine blocks autoprocessing of caspase-4/11 as well as their recognition and cleavage of gasdermin D (GSDMD). ADP-riboxanation of caspase-11 paralyses pyroptosis-mediated defence in Shigella-infected mice. Caspase-11-mediated pyroptosis has an intrinsic function of activating humoral immunity and also highlight the importance of OspC3-catalysed ADP-riboxanation for evasion of caspase-11-mediated pyroptosis by Shigella flexneri
Shigella infection-induced acute inflammatory, caspase-4-dependent epithelial cell death is counteracted by the bacterial OspC3 effector. OspC3 interacts with the caspase-4-p19 subunit and inhibits its activation by preventing caspase-4-p19 and caspase-4-p10 heterodimerization by depositing the conserved OspC3 X1-Y-X2-D-X3 motif at the putative catalytic pocket of caspase-4. The Shigella flexneri effector regulates cell death during infection. Shigella delivers a caspase-4-specific inhibitor to delay epithelial cell death and promote infection, analyzed in different human cell lines and in the guinea pig intestines model
Kobayashi, T.; Ogawa, M.; Sanada, T.; Mimuro, H.; Kim, M.; Ashida, H.; Akakura, R.; Yoshida, M.; Kawalec, M.; Reichhart, J.M.; Mizushima, T.; Sasakawa, C.
The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection
top
