WildCARDs: inflammatory caspases directly detect LPS

Abstract

Inflammasomes are sensors that serve as activation platforms for caspase-1 - a mechanism that set the prevailing paradigm for inflammatory caspase activation. A recent Nature paper by Shi et al. upends this paradigm by describing an unprecedented model for caspase activation whereby caspase-4, -5, and -11 directly bind their agonist, cytosolic LPS, triggering auto-activation and subsequent pyroptotic cell death.

Figure 1

Schematic of canonical and noncanonical inflammasome pathways for inflammatory caspase activation. Left: Inflammasomes such as AIM2, NLRP3, and NLRC4 detect contamination of the cytosol with microbial ligands (e.g., DNA, flagellin, bacterial type 3 secretion system components) or certain cellular perturbations. Via the adaptor protein ASC, they subsequently activate caspase-1 (in the case of certain CARD-containing inflammasomes, such as NLRC4, direct interaction with caspase-1 can also occur), which initiates pyroptosis and secretion of the proinflammatory cytokines IL-1β and IL-18. Right: Caspase-4, -5, and -11 directly bind cytosolic LPS from Gram-negative bacteria. They subsequently oligomerize, activate, and initiate pyroptosis.