Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation

Abstract

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. The three major components of the NLRP3 inflammasome are NLRP3, which captures the danger signals and recruits downstream molecules; caspase-1, which elicits maturation of the cytokines IL-1β and IL-18 and processing of gasdermin D to mediate cytokine release and pyroptosis; and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which functions as a bridge connecting NLRP3 and caspase-1. In this article, we review the structural information that has been obtained on the NLRP3 inflammasome and its components or subcomplexes, with special focus on the inactive NLRP3 cage, NEK7 (NIMA-related kinase 7)-licensing of NLRP3 activation, and the PYD-PYD and CARD-CARD homotypic filamentous scaffolds of the inflammasome. We further implicate structure-derived mechanisms for the assembly and activation of the NLRP3 inflammasome. Expected final online publication date for the Annual Review of Immunology, Volume 41 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Therapeutic effects of a walnut-derived peptide on NLRP3 inflammasome activation, synaptic plasticity, and cognitive dysfunction in T2DM mice

“…10,11 The NLRP3 inflammasome is a multiprotein complex comprising NLRP3, ASC (apoptosisassociated Speck-like protein containing a caspase recruitment domain), and caspase-1. 12,13 The assembled NLRP3 inflammasome can trigger the protease caspase-1 to activate gasdermin D-dependent pyroptosis and secrete proinflammatory cellular contents including interleukin (IL)-1β and IL-18, which, under normal conditions, contribute to the maintenance of homeostatic biological functions and innate immune defence. 14,15 These findings suggest that the blockade of NLRP3 inflammasome may provide a beneficial therapeutic effect against diabetes-induced nerve injuries.…”

Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors

“…13 C NMR (151 MHz, DMSO-d 6 , δ) 166.3, 153.9, 153.5, 138.8, 135.1, 130.3, 128.6, 126.8, 114.0, 103.6, 78.7, 51.2, 45.3, 29.6, 28.1, 24.5, 9.9. LC-MS (method a) m/z: 460.1 (8). 4 M HCl in dioxane (2.2 mL, 8.8 mmol) was added to a solution of 40 (100 mg, 0.22 mmol) in CH 2 Cl 2 (4.4 mL), and the resulting mixture was stirred at rt for 1 h before being concentrated, dissolved in methanol, and filtered through an ion-exchange column (Varipure IPE).…”

“…NLRP3, also known as cryopyrin, is an intracellular PRR consisting of 3 domainsan N -terminal pyrin domain, a central nucleotide-binding domain (NACHT), and a leucine-rich repeat domain. − Cytosolic NLRP3 acts as a sensor recognizing stress signals caused by PAMPs and DAMPs, and upon activation, oligomerizes and recruits ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) and procaspase-1 to form a macromolecular inflammasome complex. , This scaffold allows for proximity-based autoactivation of procaspase-1 and subsequent cleavage of pro-IL-1β, as well as pro-IL-18 and Gasdermin- d , the pyroptotic executioner protein …”

Inflammasome activation in response to aberrations of cellular homeostasis in epithelial cells from human cornea and retina

“…This leads to the destabilization of the inactive oligomer and evokes a conformational transition, resulting in the formation of an active NLRP3 oligomer (Figure 2; Hafner‐Bratkovič, 2022). It has been suggested that an LRR binding molecule, NEK7 (Schmacke et al., 2019; Sharif et al., 2019), facilitates the formation of the active conformation of NLRP3 and avoids its self‐association into inactive cages by preventing LRR‐LRR interactions (Fu & Wu, 2023; Xiao et al., 2023). The heat shock protein 90 (Hsp90) chaperone is another example, which binds to LRR and stabilizes NLRP3 by protecting it from degradation (Mayor et al., 2007).…”