Mechanisms and Consequences of Noncanonical Inflammasome-Mediated Pyroptosis

Abstract

The noncanonical inflammasome, comprising inflammatory caspases 4, 5, or 11, monitors the cytosol for bacterial lipopolysaccharide (LPS). Intracellular LPS-elicited autoproteolysis of these inflammatory caspases leads to the cleavage of the pore-forming protein gasdermin D (GSDMD). GSDMD pore formation induces a lytic form of cell death known as pyroptosis and the release of inflammatory cytokines and DAMPs, thereby promoting inflammation. The noncanonical inflammasome-dependent innate sensing of cytosolic LPS plays important roles in bacterial infections and sepsis pathogenesis. Exciting studies in the recent past have significantly furthered our understanding of the biochemical and structural basis of the caspase-4/11 activation of GSDMD, caspase-4/11's substrate specificity, and the biological consequences of noncanonical inflammasome activation of GSDMD. This review will discuss these recent advances and highlight the remaining gaps in our understanding of the noncanonical inflammasome and pyroptosis.

Keywords: LPS; caspase-11; galectin; gasdermin D; inflammasome; pyroptosis.

Figure 1.. Noncanonical inflammasome sensing of cytosolic LPS and activation of GSDMD.

LPS associated with intracellular Gram-negative bacteria or outer membrane vesicles (OMVs) gains access to the cytosol. GBPs act on the bacterial membranes to liberate LPS for recognition by the noncanonical inflammasome. The lipid A moiety of cytosolic LPS interacts with the CARD of caspase-11/4, resulting in caspase-11/4 oligomerization and activation. Active caspase-11/4 interact with GSDMD in an exosite-dependent but tetrapeptide-independent fashion and cleave it. The freed N-terminal domain of GSDMD forms of pores on the plasma membrane leading to the release of DAMPs/alarmins and the processing of IL-1β and IL-18 by the NLRP3 inflammasome. The pyroptotic cascade activates ninjurin-1, which mediates the plasma membrane rupture and terminal cell lysis (Illustration created with BioRender.com.)