Recently, Professor Zhao Wei's research group from the School of Basic Medical Sciences, Shandong University published a research paper entitled "Posttranslational ISGylation of NLRP3 by HERCs enzymes facilitates inflammasome activation in models of inflammation" in the Journal of Clinical Investigation. Postdoctor Qin Ying is the first author. Professor Zhao Wei is the corresponding author.

NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) is a crucial pattern recognition receptor, which can sense pathogen-associated molecular patterns (PAMPs) and endogenous danger signals (danger-associated molecular patterns, DAMPs) to initiate the formation of a multiprotein complex named the NLRP3 inflammasome. NLRP3 inflammasome, a crucial component of the innate immune system, induces maturation and secretion of cytokines IL-1β and IL-18, causes pyroptosis, and initiates inflammatory response. Optimal activation of the NLRP3 inflammasome is beneficial for the host to eliminate invading pathogens efficiently and quickly. However, aberrant NLRP3 inflammasome activation has been implicated in various inflammation-associated diseases, such as diabetes, atherosclerosis, obesity, cancer, and Alzheimer’s. Post-translational modifications (PTMs) of NLRP3, including ubiquitination and phosphorylation, control inflammasome activation and determine the intensity of inflammation. However, the role of other PTMs in controlling NLRP3 inflammasome activation remains unclear. This study found that toll-like receptor (TLR) priming induced NLRP3 ISGylation (a type of PTM in which ISG15 covalently binds to the target protein) to stabilise the NLRP3 protein. Viral infection, represented by SARS-COV-2 infection, and type I IFNs induced the expression of ISG15 and the predominant E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice). HERCs promoted NLRP3 ISGylation and inhibited K48-linked ubiquitination and proteasomal degradation, enhancing NLRP3 inflammasome activation. Concordantly, Herc6 deficiency ameliorated NLRP3-dependent inflammation, and hyperinflammation caused by viral infection. These results illustrate how type I IFNs responses control inflammasome activation and viral infection-induced aberrant NLRP3 activation. This work identifies ISGylation as a PTM of NLRP3 and provides a priming target for modulating NLRP3-dependent immunopathology.

Working model for HERC6 promoting NLRP3 inflammasome activation.

This work was supported by grants from the National Natural Science Foundation of China, the Newton Advanced Fellow of the Academy of Medical Sciences, and the Innovative Group Project of the Climbing Program of Shandong University.

Link to the article: https://www.jci.org/articles/view/161935