Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection

Abstract

Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8–mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME) in murine macrophages, resulting in pyroptosis. Loss of GsdmD delays membrane rupture, reverting the cell-death morphology to apoptosis. We found that the Yersinia-driven IL-1 response arises from asynchrony of macrophage death during bulk infections in which two cellular populations are required to provide signal 1 and signal 2 for IL-1α/β release. Furthermore, we found that human macrophages are resistant to YopJ-mediated pyroptosis, with dampened IL-1β production. Our results uncover a form of caspase-8–mediated pyroptosis and suggest a hypothesis for the increased sensitivity of humans to Yersinia infection compared with the rodent reservoir.

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

“…Numerous pathogens are equipped with virulence factors that inhibit host NF-jB signalling pathways. This could in turn promote caspase-8 activation and induce GSDMD cleavage and pyroptosis, as recently reported for Yersinia infection (Orning et al, 2018;Sarhan et al, 2018). However, as pyroptosis is best known as an innate immune mechanism to restrict intracellular pathogen infection, how GSDMD activation can promote host defence against Yersinia, a predominantly extracellular pathogen is unclear, and has not been formally demonstrated.…”

“…By using pharmacological inhibitors of TAK1 or IAPs (e.g. SMAC mimetics), we and others recently demonstrate that the pyroptotic effector GSDMD plays a major role in this process (Orning et al , ; Sarhan et al , ; Chen et al , ; Sanjo et al , ). Unexpectedly, under these conditions, GSDMD is processed into the lytic p30 fragment via two pathways.…”

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…31,32 Moreover, caspase-8, neutrophil elastase (NE), and cathepsin G have also been suggested to proteolytically activate GSDMD ( Figure 4). [36][37][38][39][40]…”

Guanylate-binding proteins at the crossroad of noncanonical inflammasome activation during bacterial infections

“…GSDMD is cleaved by caspase‐1 and caspase‐11 generating a C‐terminal (p20) and an N‐terminal active domain (p30) . In addition, the inhibition of TGF‐β‐activated kinase 1 activity elicits caspase‐8 cleavage of GSDMD similarly to caspase‐1 and caspase‐11 …”

“…71,72,76 In addition, the inhibition of TGF--activated kinase 1 activity elicits caspase-8 cleavage of GSDMD similarly to caspase-1 and caspase-11. 77,78 Once GSDMD cleavage occurs, the N-terminal domain is inserted into the plasmatic membrane and oligomerizes forming 10-16 nm diameter pores. 79,80 The efflux of potassium can occur through these pores triggering NLRP3/ASC inflammasome activation.…”