Human NLRP1: From the shadows to center stage

Abstract

In response to infection or cell damage, inflammasomes form intracellular multimeric protein complexes that play an essential role in host defense. Activation results in the maturation and subsequent secretion of pro-inflammatory cytokines of the IL-1 family and a specific cell death coined pyroptosis. Human NLRP1 was the first inflammasome-forming sensor identified at the beginning of the millennium. However, its functional relevance and its mechanism of activation have remained obscure for many years. Recent discoveries in the NLRP1 field have propelled our understanding of the functional relevance and molecular mode of action of this unique inflammasome sensor, which we will discuss in this perspective.

Figure 1.

NLRP1 inflammasome activation and its downstream signaling pathway. (A) Overview of the domain structure of human NLRP1 and mouse NLRP1B. (B) Overview of human NLRP1 activation by the DPP8/9 inhibitor VbP. (1) Generation of NLRP1^A and NLRP1^B by homeostatic degradation and assembly of the ternary DPP9-NLRP1^A-NLRP1^B complex. (2) Direct displacement of NLRP1^B from the DPP9 substrate tunnel leads to release of the C-terminal UPA-CARD fragments and (3) generation of an inflammasome seed. (4) Via the adaptor ASC, caspase-1 is activated. (5) Caspase-1 cleaves its substrates pro–IL-1β, which matures to pro-inflammatory IL-1β, and GSDMD, which (6) generates pores into the membrane and leads to a pyroptotic cell death.

Figure 2.

Modes of NLRP1 inflammasome activation. (A) Activation of NLRP1 by DPP8/9 inhibition. Direct displacement of the UPA-CARD fragments by DPP9 inhibition leads to inflammasome activation. (B) Activation of NLRP1 by species-specific protease cleavage events followed by the “functional degradation” of the N-terminal fragment. Human NLRP1 is activated by 3C protease (depicted here) and mouse NLRP1B by LF cleavage. (C) Activation of NLRP1 by dsRNA and conformational rearrangement. See main text for more details. Icons are depicting activatability of human or mouse NLRP1.