Pathogen blockade of TAK1 triggers caspase-8–dependent cleavage of gasdermin D and cell death

TLDR

Caspase‑8 participates in pyroptosis, and inflammasomes trigger caspase‑mediated cleavage of gasdermin D, a process previously attributed only to caspase‑1 and caspase‑11 in macrophages. The Yersinia effector YopJ blocks TAK1‑IKK signaling, causing caspase‑8 to cleave gasdermin D, inducing pyroptosis and releasing IL‑1β and IL‑18, revealing a new pathway for GSDMD activation. Orning et al., Science, p.

Abstract

Caspase-8 is a player in pyroptosis The activation of certain pattern-recognition receptors by pathogen-associated molecular patterns results in the formation of inflammasome complexes. Inflammasome complexes can initiate both the maturation of inflammatory cytokines and pyroptotic cell death via the caspase-mediated cleavage of gasdermin D (GSDMD). As of now, the only known regulators of GSDMD in macrophages are caspase-1 and caspase-11. Orning et al. report an additional pathway controlling GSDMD processing. YopJ, an effector molecule produced by Yersinia (the causative agent of plague), inhibits TAK1–IκB kinase signaling. This, in turn, results in caspase-8–directed cleavage of GSDMD, pyroptosis, and the release of interleukin 1β (IL-1β) and IL-18. Thus, in the arms race between host and pathogen, the host recognizes signaling disturbances as pathogenic and counters with inflammation and cell death. Science , this issue p. 1064