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Figure 1.
Activation of the NLRP3 inflammasome leads to cleavage of pro-IL-1β, by caspase-1, into the mature IL-1β.
Activation usually occurs through stimulation with microbial peptides, such as peptidoglycan (PGN), monosodium urate (MSU), and other pathogen-associated molecular patterns (PAMP). These PAMP are recognised by the leucine-rich repeat domain (LRR) of NLRP3. Mutations in the NACHT domain of NLRP3 cause spontaneous activation of the this multimeric protein complex, which leads to over-production of IL-1β. This excessive secretion of IL-1β is mainly responsible for the clinical manifestations of the cryopyrinopathies (CAPS) and plays a role in all periodic fevers. Screening for mutations in the NACHT domain of NLRP3 is routinely carried out for diagnosis of CAPS; however mutations are only found in around 50% of cases. ASC, apoptosis-associated speck-like protein containing a CARD; bZIP, basic leucine zipper; CARD, caspase recruitment domain; CC, coiled coil; FIIND, function to find domain; MDP, muramyl dipeptide; PYD, pyrin domain; SPRY, spIA/ryanodine receptor domain. |
