Shigella flexneri evades septin-mediated cell-autonomous immunity via protein ADP-riboxanation.

Cell-autonomous immunity represents evolutionarily conserved defense mechanisms present in both immune and non-immune cells. One of such mechanisms is mediated by cytoskeletal septins that entrap cytosolic bacterial pathogens within cage-like structures. To promote infection, Shigella flexneri delivers effector proteins directly into host cells via a type III secretion system. Here we demonstrate that OspC effectors enable Shigella flexneri to evade septin cage entrapment. Mechanistically, OspC catalyzes ADP-riboxanation of SEPT9 at Arg561, a site essential for stabilizing septin hetero-oligomers. Notably, Arg561 ADP-riboxanation impairs septin polymerization and hence assembly of higher-order structures, including filaments and cage-like structures. Furthermore, we provide evidence that OspC effectors act synergistically with OspG to antagonize septin cage entrapment via two distinct post-translational modifications, thereby facilitating cell-to-cell spread and intracellular replication. Overall, our work reveals the elegant strategies of bacterial pathogens to evade septin-mediated cell-autonomous immunity and offers avenues for therapeutic intervention.