Posttranslational Regulation of Inflammasomes, Its Potential as Biomarkers and in the Identification of Novel Drugs Targets

Abstract

In this review, we have summarized classical post-translational modifications (PTMs) such as phosphorylation, ubiquitylation, and SUMOylation of the different components of one of the most studied NLRP3, and other emerging inflammasomes. We will highlight how the discovery of these modifications have provided mechanistic insight into the biology, function, and regulation of these multiprotein complexes not only in the context of the innate immune system but also in adaptive immunity, hematopoiesis, bone marrow transplantation, as well and their role in human diseases. We have also collected available information concerning less-studied modifications such as acetylation, ADP-ribosylation, nitrosylation, prenylation, citrullination, and emphasized their relevance in the regulation of inflammasome complex formation. We have described disease-associated mutations affecting PTMs of inflammasome components. Finally, we have discussed how a deeper understanding of different PTMs can help the development of biomarkers and identification of novel drug targets to treat diseases caused by the malfunctioning of inflammasomes.

Double Targeting Inflammasome Activation and Accelerated Cellular Senescence in Alveolar Macrophages Exposed to Cigarette Smoke and COPD

“…Whether the NLRP3 inflammasome pathway is activated in COPD and/or response to cigarette smoke exposure remains a debatable issue (see review [26]). While multiple evidence from human [22; 59] and animal studies [59][60][61] lends support for a "Yes" answer, other studies present opposite results [62][63][64][65][66], As a potent protective mechanism but potentially detrimental at excessive activation, the NLRP3 inflammasome pathway is tightly controlled by multiple regulatory pathways acting on post-translational modifications of proteins as well as transcription and translation levels [67][68][69]. In this relation cigarette smoke could inhibit the inflammasome by upregulated catabolism of NLRP3 [64].…”

The Role of Post-Translational Modifications in Regulation of NLRP3 Inflammasome Activation

“…Ser803 phosphorylation may support TGN dispersion by stabilizing the double-ring cage structure [ 97 ]. Additionally, phosphomimetic substitutions of Ser803 impair the NEK7 recruitment to NLRP3 in vitro and in vivo, as well as the BRCC3-mediated NLRP3 deubiquitination [ 95 , 98 ]. Casein kinase 1 alpha 1 (CSNK1A1) serves as the key kinase that targets NLRP3 phosphorylation at Ser803 [ 95 ].…”

Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations

“…104 These epigenetic changes can also affect immune signaling pathways, leading to dysregulation of immune responses. 105 Histones are proteins that govern DNA packaging into a compact structure called chromatin. Modifications to histones, such as acetylation, methylation, and phosphorylation, can alter the accessibility of genes for transcription.…”

“…106 Histone modifications can have an impact on the inflammation resolution process 104 and immune signaling pathways, resulting in dysregulation of immune responses. 105 Noncoding RNAs, such as microRNAs and long noncoding RNAs, are involved in the regulation of gene expression. According to the current understanding, they can act as fine-tuners of inflammatory responses by either promoting or inhibiting the expression of pro-inflammatory or anti-inflammatory genes.…”