NLRP3 Gene

The NLRP3 gene (NLRP3 stands for "NLR Family Pyrin Domain Containing 3") is a protein-coding gene located on chromosome 1q44. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene.

The NLRP3 gene encodes a "pyrin-like" protein (NLRP3 protein) that contains a pyrin domain, a nucleotide-binding site (NBS) domain and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NLRP3 inflammasome complex. The NLRP3 inflammasome complex functions as an upstream activator of NF-kappaB signaling and plays a role in the regulation of inflammation, immune response and apoptosis.

As a sensing component of the NLRP3 inflammasome, the NLRP3 protein plays a crucial role in innate immunity and inflammation. It initiates the formation of the polymeric inflammasome complex, which consists of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5), in response to pathogens (and other pathogens).

Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion into the extracellular milieu. Inflammasomes can also trigger pyroptosis, an inflammatory form of programmed cell death.

Under resting conditions, NLRP3 is autoinhibited. Stimuli for NLRP3 activation include extracellular ATP, reactive oxygen species, K(+) efflux, monosodium urate or cholesterol crystals, amyloid beta fibers, environmental or industrial particles and nanoparticles, cytosolic dsRNA, etc. However, it is still unclear what the direct NLRP3 activator is.

NLRP3 protein regulates T helper 2 (Th2) cell differentiation independently of inflammasome activation and plays a role in Th2 cell-dependent asthma and tumor growth. During Th2 differentiation, the protein is required for optimal IRF4 binding to the IL4 promoter and for IRF4-dependent IL4 transcription.

Mutations in the NLRP3 gene are associated with the following diseases:

• FCAS (Familial autoinflammatory cold syndrome)
• Muckle-Wells syndrome (MWS)
• CINCA syndrome(chronic infantile neurological cutaneous and articular syndrome)
• NOMID (neonatal multisystem inflammatory disease)
• Hereditary keratoendotheliitis fugax
• Autosomal dominant deafness 34

SARS-CoV 3a protein, a transmembrane pore-forming viroporin, has been shown to activate the NLRP3 inflammasome via ion channel formation in macrophages

1. Kelley N et al (2019) The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci 20: 3328.
2. Shao BZ et al (2015) NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol 6:262.