Regulation of NLRP3 Inflammasome by Phosphorylation

Abstract

The cytosolic pattern recognition receptor (PRR) NOD-like receptor family, pyrin domain containing 3 (NLRP3) senses a wide range of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Upon activation, NLRP3 triggers the assembly of inflammasome via the self-oligomerization and the recruitment of apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and pro-caspase-1, facilitating the robust immune responses including the secretion of proinflammatory cytokines and pyroptosis. The NLRP3 inflammasome must be well orchestrated to prevent the aberrant activations under physiological and pathological conditions, because uncontrolled activation of NLRP3 inflammasome is one of the major causes of a variety of autoimmune diseases and metabolic disorders. Therefore, understanding the molecular mechanisms for controlling NLRP3 inflammasome activation may provide novel strategies for the treatment of NLRP3-related diseases. Although NLRP3 inflammasome can be regulated at the transcriptional level, the post-translational modification (PTM) of NLRP3 as well as other inflammasome components has also been showed to be critical for the regulation of its activation. Several kinases and phosphatases have been shown to control NLRP3 inflammasome activation in response to either exogenous pathogen infections or endogenous molecules, such as bile acids. In this review, we summarize our current knowledge of phosphorylation patterns and their functional role in the regulation of NLRP3 inflammasome, and suggest interesting areas for future research.

Acetylation is required for NLRP3 self-aggregation and full activation of the inflammasome

“…Together with others findings that targeting the PTMs of NLRP3 may providing a potential for treating NLRP3 associated diseases (8,9,12,25), In our study, KAT5 specific inhibitor-NU9056 could suppress the NLRP3 inflammasome activation both in vitro and in vivo by inhibiting NLRP3 acetylation. Taken together, our study adds a new view for NLRP3 full activation and suggests targeting NLRP3 acetylation may provide a new approach for treatment of NLRP3 associated diseases.…”

“…Since then, a number of E3 ligases have been identified for promoting K48-linked ubiquitination and degradation of NLRP3, such as PAI2(26), MARCH7(24), Trim31(27) and FBXL2(28). Except for ubiquitination, phosphorylation of NLRP3 by different kinases have been widely studied (3,8,9). Undoubtedly, these studies broadening our understanding of the NLRP3 activation, however, most of which focused on how priming signal-induced phosphorylation of NLRP3 and associated activity (10)(11)(12).…”

“…Recent studies have provided a molecular mechanism for NLRP1B activation (6,7), in which they have found ubiquitination on N terminal of NLRP1B promotes the degradation of N terminus and frees the NLRP1B C terminus to activate caspase-1, suggesting modulation of post-translational modifications (PTMs) is critical for inflammasome activation. Although there are several PTMs on NLRP3 were reported, such as ubiquitylation, phosphorylation and sumoylation (3,8,9),these studies mostly focused on the PTMs induced by the priming signal (10)(11)(12), the second signal induced PTMs on NLRP3 and associated activities changed remains less defined.…”

STING recruits NLRP3 to the ER and deubiquitinates NLRP3 to activate the inflammasome

“…Here we find that STING promotes NLRP3 translocation to the ER and facilitates the inflammasome activation. Moreover, post-translational modifications of NLRP3 are critical for its activation, including phosphorylation (Song & Li, 2018), SUMOylation (Barry et al, 2018), and ubiquitination (Py et al, 2013). MARCH7 and TRIM31 facilitate NLRP3 ubiquitination and proteasomal degradation (Song et al, 2016; Yan et al, 2015).…”

Ibrutinib alleviated LPS-induced neuroinflammation and synaptic defects in a mouse model of depression

“…LPS may activate in ammasome via NRLP3 and its linked signaling molecules including p38 and caspase-1 regulation [55][56][57][58][59][60], which subsequently play a signi cant role in neuroin ammation and neurotoxicity. In our results, enhanced p-p38, caspase-1, and NRLP3 expression were detected in LPS treated mice hippocampus (Fig.…”