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.
Highlights
Inflammasomes are large multi-protein complexes that mediate the immune responses against pathogen infection and tissue damage [1, 2]
This study suggested that TGF-β-activated kinase 1 (TAK1), the mitogen-activated protein kinase kinase kinase (MAPKKK), or other Toll-like receptor (TLR) signaling-related kinase(s), may phosphorylate NLRP3 or other inflammasome components, which serves as a rapid but essential step for NLRP3 priming
Hara et al suggested that Syk/Jun Nterminal kinase 1 (JNK1)/JNK2-mediated a caspase-recruitment domain (ASC) phosphorylation plays a role in the pyroptosome formation of NLRP3 and Absent in Melanoma 2 (AIM2), but not NLRC4, inflammasome [37]
Summary
Inflammasomes are large multi-protein complexes that mediate the immune responses against pathogen infection and tissue damage [1, 2]. Several inflammasome components, such as the core PRRs like NLRP3, NLRC4, Pyrin, the adaptor ASC, and the effector caspase-1, are all reported to be regulated by phosphorylation [32, 35,36,37,38,39,40,41,42,43,44]. This study suggested that TGF-β-activated kinase 1 (TAK1), the mitogen-activated protein kinase kinase kinase (MAPKKK), or other TLR signaling-related kinase(s), may phosphorylate NLRP3 or other inflammasome components, which serves as a rapid but essential step for NLRP3 priming.
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