Abstract
The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multi-protein complex that can be activated by a variety of pathogen-associated molecular patterns or damage-associated molecular patterns. Inappropriate NLRP3 inflammasome activation can induce autoinflammatory, autoimmune, or metabolic disorders. Therefore, NLRP3 is an attractive target against NLRP3 inflammasome activation, and specific targeting of NLRP3 might be an intriguing approach to the development of drugs for the treatment of NLRP3 inflammasome-related diseases. Although many studies with varied mechanistic approaches were reported in inhibition of NLRP3 inflammasome activation, mechanisms related to regulation of posttranslational modification (PTM) of NLRP3, as a focal point has not been thoroughly addressed. Recently, extensive investigations of PTMs of NLRP3 have led to partial understanding of the mechanisms involved in NLRP3 inflammasome activation. In this review, we focused on the role of PTMs regulating NLRP3 inflammasome activation.
Highlights
Inflammasomes are unique, complex structures formed by proteins in cytosol
The autoinflammatory syndromes associated with gain-of-function mutations of NOD-like receptor family pyrin domain-containing 3 (NLRP3) leads to abnormal NLRP3 inflammasome activation causing cryopyrin-associated periodic syndromes (CAPS), a group of rare, inherited, auto-inflammatory diseases, such as Muckle–Wells syndrome, familial cold urticaria, and neonatal onset multisystem inflammatory disease (NO-MID) [12, 13]
Many types of posttranslational modification (PTM), such as phosphorylation, ubiquitination, alkylation, and S-nitrosylation have been detected in NLRP3, and these PTMs play important roles in NLRP3 inflammasome activation [24]
Summary
Inflammasomes are unique, complex structures formed by proteins in cytosol. Inflammasome activation results in the recruitment and activation of caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their active forms. Many types of PTMs, such as phosphorylation, ubiquitination, alkylation, and S-nitrosylation have been detected in NLRP3, and these PTMs play important roles in NLRP3 inflammasome activation [24]. Phosphorylation of the Y861 residue at the LRR domain of NLRP3 negatively regulates NLRP3 inflammasome activation, but NLRP3 inflammasome stimulators, such as ATP, MSU crystals, and silica crystals, induce tyrosine dephosphorylation of NLRP3 at Y861 in a PTPN22-dependent manner, leading to activation of NLRP3 [25]. PTPN22 deficiency prevents MSU-induced peritonitis in mice by inhibition of inflammasome-dependent IL-1β production [25] PGE2mediated EP4 signaling causes PKA–NLRP3 interactions, and subsequently activates PKA, phosphorylates NLRP3 within the NBD at S295 by increasing cytoplasmic cAMP levels (Table 1; Figure 1).
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