Abstract
In response to diverse pathogenic and danger signals, the cytosolic activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing (3)) inflammasome complex is a critical event in the maturation and release of some inflammatory cytokines in the state of an inflammatory response. After activation of the NLRP3 inflammasome, a series of cellular events occurs, including caspase 1-mediated proteolytic cleavage and maturation of the IL-1β and IL-18, followed by pyroptotic cell death. Therefore, the NLRP3 inflammasome has become a prime target for the resolution of many inflammatory disorders. Since NLRP3 inflammasome activation can be triggered by a wide range of stimuli and the activation process occurs in a complex, it is difficult to target the NLRP3 inflammasome. During the activation process, various post-translational modifications (PTM) of the NLRP3 protein are required to form a complex with other components. The regulation of ubiquitination and deubiquitination of NLRP3 has emerged as a potential therapeutic target for NLRP3 inflammasome-associated inflammatory disorders. In this review, we discuss the ubiquitination and deubiquitination system for NLRP3 inflammasome activation and the inhibitors that can be used as potential therapeutic agents to modulate the activation of the NLRP3 inflammasome.
Highlights
Innate immune signaling plays a protective role against pathogens and mediates an inflammatory state that has been linked with many inflammatory diseases [1]
We focus on NLRP3 inflammasome activation regulation by the ubiquitination system and the potential pharmacological inhibitor of NLRP3 regulation through the ubiquitin system, which could have therapeutic implications for NLRP3 inflammasome-associated diseases
As K48-linked ubiquitination is linked with protein degradation, the UAF1/Ubiquitin specific peptidase 1 (USP1) complex stabilizes the degradation of NLRP3, which increases cellular NLRP3 levels and promotes NLRP3 inflammasome activation
Summary
Innate immune signaling plays a protective role against pathogens and mediates an inflammatory state that has been linked with many inflammatory diseases [1]. The effector responses caused by the innate immune system are induced by various pattern recognition receptors (PRRs), which can detect endogenous danger signals (danger-associated molecular patterns—DAMPs) or exogenous signals NLRP3 regulates the immune response against a wide range of stimuli that can be found endogenously due to aging [5]. The NLRP3 inflammasome contributes to the pathogenesis of age-associated diseases such as atherosclerosis, type 2 diabetes, and gouty arthritis [6]. The molecular mechanisms of NLRP3 inflammasome activation and how they are linked with disease pathogenesis are emerging topics of research interest. A comprehensive understanding of the ubiquitin system’s regulation of the NLRP3 inflammasome cascade may contribute to targeted therapeutic interventions for NLRP3 inflammasome-mediated diseases. We focus on NLRP3 inflammasome activation regulation by the ubiquitination system and the potential pharmacological inhibitor of NLRP3 regulation through the ubiquitin system, which could have therapeutic implications for NLRP3 inflammasome-associated diseases
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