NLRP1- A CINDERELLA STORY: a perspective of recent advances in NLRP1 and the questions they raise

Abstract

NLRP1, while the first inflammasome described, has only recently begun to gain significant attention in disease pathology, inflammation research, and potentially, as a therapeutic target. Recently identified human variants provide key insights into NLRP1 biology while its unique expression in barrier cells such as keratinocytes and airway epithelial cells has aligned with new, human specific agonists. This differentiates NLRP1 from other inflammasomes such as NLRP3 and identifies it as a key therapeutic target in inflammatory diseases. Indeed, recent discoveries highlight that NLRP1 may be the predominant inflammasome in human barrier cells, its primary role akin to NLRP3, to respond to cellular stress. This review focuses on recent studies identifying new human-specific NLRP1 mechanisms of activation of, gain-of-function human variants and disease, its role in responding to cellular stress, and discuss potential advances and the therapeutic potential for NLRP1.

Fig. 1. Schematic representation of NLRP1.

a A comparison of architectural differences between mouse and human NLRP1. b Representation of the activating and restraining/inhibitory functions of NLRP1. Consistent between species, NLRP1 is constrained in an inactive form via DPP8/9 interaction with the FIIND domain, the inhibition of which by Val-boroPro (also called Talabostat) disengages DPP8/9 association inducing functional degradation and subsequent formation of an active inflammasome complex, while oxidized thioredoxin restrains NLRP1 activity via interaction with the NACHT-LRR domain. NLRP1 is also restrained by thioredoxin-1 (TRX1) which interacts with the NACHT/LRR domains while in response to ribotoxic stress, ZAKα and p38 MAP kinase induce phosphorylation of the disordered inter-region between the Pyrin and NACHT domains, mediating activation of NLRP1 and formation of a functional inflammasome complex. The small compound inhibitor ADS032 targets the Walker B motif within the NACHT domain to inhibit NLRP1 activation. The role of NLRP1 in disease is highlighted by gain of function mutations (marked in green: refer to Supplementary Table 1) in functional domains of NLRP1, while a loss of function variant in DPP8/9 (red) induces constitutive NLRP1 activity.

Fig. 2. Cellular redundancy amongst inflammasomes converges upon NLRP1 in a cell-specific manner.

While nigericin and dsDNA are considered prototypic NLRP3 and AIM2 in macrophages, in the absence of NLRP3 or AIM2, subsequent ribotoxic stress induces ZAKα-mediated activation of NLRP1. Created with BiorRender.com.