NLRP1

This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. The NLRP1 protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined.[7]

NLRP1 activates an antibacterial immune response. Antibacterial immune response compensates for the loss of the MAP kinase response. Humans produce NLRP1, but human NLRP1 is not activated by lethal factor.[8] NLRP1 could be activated by proteolytic cleavage resulting in the removal of an auto-inhibitory PYD and release of the CARD domain, responsible for the recruitment and activation of pro-caspase-1 in the active form of caspase-1.[8] But the mechanism of human NLRP1 activation and the function in immunity is not clear.[8]

NLRP1 has been shown to interact with caspase 9[11][12] and APAF1.[11]

Mice have three paralogs of the Nlrp1 gene (Nlrp1a, b, c). Nlrp1c is a pseudogene.[13] Mouse NLRP1B is not activated by a receptor-ligand type mechanism. NLRP1B variants from certain inbred mouse strains, BALB/c and 129, can be activated by the lethal factor (LF) protease. The lethal factor protease is produced and secreted by Bacillus anthracis, the agent of anthrax.[14] Together with protective antigen (PA), LF forms a bipartite toxin, Lethal Toxin. The role of PA is to form a translocation channel that delivers LF into the host cell cytosol, where LF play roles in immune response by cleaving and inactivating MAP kinases.[15][16] LF also directly cleaves NLRP1B proximal to its N-terminus, it is necessary and sufficient for NLRP1B inflammasome formation and CASP1 activation.[17] Activation of NLRP1B-dependent inflammasome responses appears in host defense with mechanism like IL-1β and neutrophils.[18][19] NLRP1B can function as a sensor of bacterial proteases, immune responses are specifically activated by virulence factors.[20][21]

It is not clear what stimuli might activate NLRP1A, the other known functional murine NLRP1 paralog. The study identified a mouse carrying a missense gain-of-function mutation in NLRP1A (Q593P) that active inflammasome responses. The mechanism of wild-type NLRP1A activation is unclear.[22]

• Overview of all the structural information available in the PDB for UniProt: Q9C000 (NACHT, LRR and PYD domains-containing protein 1) at the PDBe-KB.