J Clin Invest. 2023 Oct 16;133(20):e161935. doi: 10.1172/JCI161935.
The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system that initiates inflammatory responses. Posttranslational 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 TLR priming induced NLRP3 ISGylation (a type of PTM in which ISG15 covalently binds to the target protein) to stabilize the NLRP3 protein. Viral infection, represented by SARS-COV-2 infection, and type I IFNs induced 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, resulting in the enhancement of NLRP3 inflammasome activation. Concordantly, Herc6 deficiency ameliorated NLRP3-dependent inflammation as well as hyperinflammation caused by viral infection. The results illustrate the mechanism by which type I IFNs responses control inflammasome activation and viral infection-induced aberrant NLRP3 activation. This work identifies ISGylation as a PTM of NLRP3, revealing a priming target that modulates NLRP3-dependent immunopathology.
NOD、LRR 和 pyrin 结构域包含蛋白 3（NLRP3）炎症小体是先天免疫系统的关键组成部分，它启动炎症反应。NLRP3 的翻译后修饰（PTMs），包括泛素化和磷酸化，控制炎症小体的激活并决定炎症的强度。然而，其他 PTMs 在控制 NLRP3 炎症小体激活中的作用尚不清楚。本研究发现 TLR 引发诱导 NLRP3 的 ISGylation（一种 ISG15 共价结合靶蛋白的 PTM）来稳定 NLRP3 蛋白。以 SARS-COV-2 感染为代表的病毒感染和 I 型干扰素诱导 ISG15 的表达和主要的 E3 ISGylation 连接酶 HECT 结构域和 RCC1 样结构域包含蛋白（HERCs；人 HERC5 和鼠 HERC6）。HERCs 促进 NLRP3 的 ISGylation 并抑制 K48 连接的泛素化和蛋白酶体降解，从而增强 NLRP3 炎症小体的激活。相应地，Herc6 缺陷减轻了 NLRP3 依赖性炎症以及病毒感染引起的过度炎症。结果说明了 I 型干扰素反应控制炎症小体激活和病毒感染诱导的异常 NLRP3 激活的机制。本工作鉴定了 ISGylation 作为 NLRP3 的一种 PTM，揭示了一种调节 NLRP3 依赖性免疫病理学的引发靶标。
