The Role of Post-Translational Modifications in Regulation of NLRP3 Inflammasome Activation

Abstract

Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) induce NLRP3 inflammasome activation, and subsequent formation of active caspase-1 as well as the maturation of interleukin-1β (IL-1β) and gasdermin D (GSDMD), mediating the occurrence of pyroptosis and inflammation. Aberrant NLRP3 inflammasome activation causes a variety of diseases. Therefore, the NLRP3 inflammasome pathway is a target for prevention and treatment of relative diseases. Recent studies have suggested that NLRP3 inflammasome activity is closely associated with its post-translational modifications (PTMs). This review focuses on PTMs of the components of the NLRP3 inflammasome and the resultant effects on regulation of its activity to provide references for the exploration of the mechanisms by which the NLRP3 inflammasome is activated and controlled.

Tau induces inflammasome activation and microgliosis through acetylating NLRP3

“…Meanwhile, we also verified that hippocampal NLRP3 acetylation level was up‐regulated in Tauopathy transgenic mice and AD patients. It has been reported that PTMs of NLRP3 such as acetylation play a vital role in regulating NLRP3 inflammasome activation 39,40 . Therefore, these results stand for a hypothesis that NLRP3 inflammasome activation in Tauopathy transgenic mice and AD patients is mediated by NLRP3 acetylation, which is partly illustrated by the high correlation between NLRP3 acetylation level and IL‐1β or cleaved Caspase‐1 level.…”

“…It has been reported that PTMs of NLRP3 such as acetylation play a vital role in regulating NLRP3 inflammasome activation. 39,40 Therefore, these results stand for a hypothesis that NLRP3 inflammasome activation in Tauopathy transgenic mice and AD patients is mediated by NLRP3 acetylation, which is partly illustrated by the high correlation between NLRP3 acetylation level and IL-1β or cleaved Caspase-1 level. Since Tau was identified as a bona fide acetyltransferase with enzymatic activity resides within the microtubule-binding regions, 43 it is thus reasonable to speculate that Tau protein may induce NLRP3 acetylation in Tauopathies.…”

“…38 Several types of posttranslational modifications (PTMs) such as phosphorylation/dephosphorylation, ubiquitination/deubiquitination, acetylation/deacetylation, SUMOylation and nitrosylation, and protein-protein interactions of NLRP3 inflammasome components license/limit cells for full activation of inflammasome assembly. 39,40 A recent study showed that suppression of NAD-dependent deacetylase Sirtuin-2 mediated acetylation of NLRP3 and promoted NLRP3 inflammasome activation, thus contributing to ageing-associated inflammation and insulin resistance. 41 Moreover, nigericin can trigger acetyltransferase KAT5-mediated NLRP3 acetylation to induce NLRP3 self-aggregation and full activation of the inflammasome.…”

“…Canonical full activation of the NLRP3 inflammasome is regulated by a two‐step process consisting of a priming step at the transcriptional and posttranslational levels, and an activation/assembly step 38 . Several types of posttranslational modifications (PTMs) such as phosphorylation/dephosphorylation, ubiquitination/deubiquitination, acetylation/deacetylation, SUMOylation and nitrosylation, and protein–protein interactions of NLRP3 inflammasome components license/limit cells for full activation of inflammasome assembly 39,40 . A recent study showed that suppression of NAD‐dependent deacetylase Sirtuin‐2 mediated acetylation of NLRP3 and promoted NLRP3 inflammasome activation, thus contributing to ageing‐associated inflammation and insulin resistance 41 .…”

cFLIPL alleviates myocardial ischemia‐reperfusion injury by regulating pyroptosis

“…Acute occlusion of the coronary artery, oxidative stress, calcium overload, and adenosine triphosphate (ATP) overload occur when blood supply is restored after effective reperfusion measures Yang et al, 2018;Zhuang et al, 2023). The resulting cell debris and various inflammatory factors recognize pathogen-associated molecular patterns (PAMPs) or dangerassociated molecular patterns (DAMPs), recruiting adaptor proteins such as ASC containing a caspase-recruitment domain (ASC) and effector Caspase 1 to assemble the NLRP3 inflammasome (Xia et al, 2023;Zhan et al, 2022;. Caspase 1 undergoes self-cleavage into the enzymatically active cleaved Caspase 1, activating intracellular inflammatory responses (Hou et al, 2023).…”