NLRP3 Ubiquitination—A New Approach to Target NLRP3 Inflammasome Activation

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.

Potential Combination Drug Therapy to Prevent Redox Stress and Mitophagy Dysregulation in Retinal Müller Cells under High Glucose Conditions: Implications for Diabetic Retinopathy

“…However, the feedback regulation of the NLRP3 inflammasome, its degradation, and inflammation resolution are still to be revealed. In this regard, Parkin has been suggested to be involved in NLRP3 inflammasome ubiquitination and its autophagic degradation involving p62 and LC3BII autophagosome [ 51 , 52 ]. We also observed that Parkin knockdown by siRNA reduces mitophagy, but mitochondrial fragmentation remains in rMC1 under HG while TFEB and PGC1α nuclear translocation is prevented (data not shown).…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…The formation of condensates during LLPS is a process of nucleation and growth constrained by an energy barrier that can usually be breached by thermodynamic nonequilibrium PTMs [ 269 , 302 ]. Many well-known targets of melatonin including NLRP3 inflammasome [ 303 , 304 , 305 ] and tumor suppressor protein p53 [ 306 , 307 , 308 ] contain prion-like IDRs that facilitate LLPS [ 265 , 309 , 310 , 311 ] and are regulated by ATP-dependent PTMs such as phosphorylation, ubiquitination, and SUMOylation [ 312 , 313 , 314 , 315 , 316 , 317 ], while DEAD-box RNA helicases such as DDX3X, which are tuned by RNA and ATP [ 318 ], can critically determine the outcome of prionoid LLPS in NLRP3 [ 310 ]. Posttranslational modification of PrP C initiates and/or propagates PrP Sc aggregates [ 319 , 320 ], profoundly altering prion assembly pathways [ 321 ] to produce new strains with different protein conformations in vivo [ 322 ].…”

NLRP3 Inflammasome in Vascular Disease: A Recurrent Villain to Combat Pharmacologically

“…Furthermore, the activation of the NLRP3 inflammasome is tightly regulated through a two-step process ( Figure 1 ): (1) priming and (2) assembly and activation [ 10 ]. The priming signal initiates a sequence of events to upregulate the insufficient levels of NLRP3 components existing in the cells at the resting state [ 16 ]. This transcriptional upregulation can be induced by diverse damaged-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) through various PRRs including TLRs, NLRs, and cytokines’ receptors, which result in nuclear factor-κB (NF-κB) activation and gene transcription of NLRP3 as well as main pro-inflammatory genes, such as pro-IL-1β [ 16 ].…”

“…The priming signal initiates a sequence of events to upregulate the insufficient levels of NLRP3 components existing in the cells at the resting state [ 16 ]. This transcriptional upregulation can be induced by diverse damaged-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) through various PRRs including TLRs, NLRs, and cytokines’ receptors, which result in nuclear factor-κB (NF-κB) activation and gene transcription of NLRP3 as well as main pro-inflammatory genes, such as pro-IL-1β [ 16 ]. During this step, NLRP3 is still controlled through a combination of post-translational modifications (PTMs), which have been identified to be crucial in regulating NLRP3 inflammasome activation [ 10 ].…”

“…Of these modifications, phosphorylation can induce or inhibit activation depending on the site and stage of NLRP3 activation [ 17 ]. Furthermore, ubiquitination and deubiquitination have an essential role in the degradation and activation of NLRP3 [ 16 ]. Accordingly, NLRP3 remains in an auto-suppressed inactive state, prepared to receive the activation signal [ 10 , 16 ].…”