NLRP11 is Essential for NLRP3 Inflammasome Activation

Gangopadhyay, Anu

doi:https://doi.org/10.21985/n2-vnne-dw35

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NLRP11 is Essential for NLRP3 Inflammasome Activation

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Inflammasomes are intracellular multiprotein signaling complexes that link Pathogen Associated and Danger Associated Molecular Patterns (PAMPs and DAMPs) by Pattern Recognition Receptors (PRRs) to the activation of Caspase-1, leading to the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and the induction of pyroptosis. Nucleotide-binding oligomerization domain (NOD)-like containing a PYRIN domain (PYD) 3 (NLRP3) is the most well characterized inflammasome forming PRR and recruits the common adaptor protein, apoptosis-associated speck like protein containing a caspase recruitment domain, (ASC), to activate caspase-1 at the mitochondria. Dysfunction of NLRP3 is involved in microbial infections, metabolic and inflammatory diseases, and cryopyrinopathies. Potassium efflux is thought to be a unifying step that is essential for NLRP3 inflammasome activation induced by various stimuli. Despite extensive study of this protein, the exact molecular mechanism leading to NLRP3 activation remains elusive. Here I report the identification of a protein evolved specifically in humans, NLRP11, as an essential modulator for NLRP3 inflammasome activation in human monocytes and macrophages. NLRP11 functions as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NLRP11, ASC recruitment, caspase-1 activation, and IL-1β secretion are abrogated. Upon activation, NLRP3-NLRP11 interact and subsequently form a high NLRP3-NLRP11 molecular weight complex. These studies demonstrate that NLRP11 is essential for NLRP3 inflammasome activation and may serve as a potential therapeutic target for various inflammatory disorders.

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