Fig. 12

Proposed mechanism of apoptosis inhibition and pyroptosis activation. After N. meningitidis infection, HrpA-DYNLT1 interaction allows the translocation of PorB to the mitochondria and its interaction with the voltage-dependent anion-selective channel (VDAC). This interaction determines inhibition of pro-caspase-9 cleavage and of activation of downstream pathway until PARP-1 and, hence, inhibition of apoptosis. N. meningitidis can expose the cytosolic lipooligosaccharide (LOS) and induce the non-canonical inflammasome pathway determining cleavage of caspase-11 in mouse and caspase-4/5 in human. Gasdermin D (GSDMD) is an effector of pyroptosis and, after cleavage, its N-terminal domain constitutes a membrane pore to favor secretion of inflammatory mediators. In the proposed model, GSDMD is inhibited by high caspase-3 levels which are involved, instead, in the activation of Gasdermin E (GSDME). Like the GSDMD, GSDME is activated by N-terminal cleavage determining membrane pore assembly to mediate efflux of activate interleukins and induce inflammation and pyroptosis. Damage-associated molecular patterns (DAMPs) derived by dead cells induce activation of inflammasome with consequent caspase-1 activation. Also in this case the effect is aborted as a consequence of the caspase- 3 inhibition on GASDMD. Created with BioRender.com