Autolytic Proteolysis within the Function to Find Domain (FIIND) Is Required for NLRP1 Inflammasome Activity

Abstract

Nucleotide-binding domain leucine-rich repeat proteins (NLRs) play a key role in immunity and disease through their ability to modulate inflammation in response to pathogen-derived and endogenous danger signals. Here, we identify the requirements for activation of NLRP1, an NLR protein associated with a number of human pathologies, including vitiligo, rheumatoid arthritis, and Crohn disease. We demonstrate that NLRP1 activity is dependent upon ASC, which associates with the C-terminal CARD domain of NLRP1. In addition, we show that NLRP1 activity is dependent upon autolytic cleavage at Ser(1213) within the FIIND. Importantly, this post translational event is dependent upon the highly conserved distal residue His(1186). A disease-associated single nucleotide polymorphism near His(1186) and a naturally occurring mRNA splice variant lacking exon 14 differentially affect this autolytic processing and subsequent NLRP1 activity. These results describe key molecular pathways that regulate NLRP1 activity and offer insight on how small sequence variations in NLR genes may influence human disease pathogenesis.

NLRP1 Is an Inflammasome Sensor for Toxoplasma gondii

“…When 293T cells were transiently transfected with NLRP1b 129 , both the 160-kDa full-length protein and the ϳ140-kDa fragment, the result of FIIND domain auto-proteolysis that is necessary but not sufficient for sensor activation, were detected ( Fig. 4E and B) (31). As previously reported, lethal factor treatment led to accumulation of an N-terminal ϳ35-kDa fragment (Fig.…”

The Therapeutic Potential of Modifying Inflammasomes and NOD-Like Receptors

“…Inhibition of K + efflux or P2X7R blockade with selective antagonists abrogated LT-stimulated inflammasome activation. It has also been proposed that NLRP1 activity can be triggered by autoproteolytic processing within FIIND (Finger et al, 2012). This The Inflammasomes finding is of interest in view of the observation that LTinduced Nlrp1 activation is susceptible to inhibition by protease inhibitors (Levinsohn et al, 2012).…”

International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease

“…Polymorphic and engineered variation to the identified cleavage site led to alterations in cellular sensitivity to lethal toxin and subsequent changes in NLRP1 inflammasome activation. It has also been suggested that NLRP1 undergoes spontaneous selfcleavage in the C-terminal function to find domain and that this process is required for full activation of the inflammasome (D'Osualdo et al, 2011;Finger et al, 2012). To date similar requirements for receptor cleavage have not been described in other inflammasome-forming proteins, highlighting the diverse cellular processes that have evolved to activate caspase-1.…”