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Posttranslational ISGylation of NLRP3 by HERC enzymes facilitates inflammasome activation in models of inflammation
Ying Qin, … , Chunyuan Zhao, Wei Zhao
Ying Qin, … , Chunyuan Zhao, Wei Zhao
Published August 31, 2023
Citation Information: J Clin Invest. 2023;133(20):e161935. https://doi.org/10.1172/JCI161935.
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Research Article Immunology Inflammation Article has an altmetric score of 1

Posttranslational ISGylation of NLRP3 by HERC enzymes facilitates inflammasome activation in models of inflammation

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Abstract

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.

Authors

Ying Qin, Xintong Meng, Mengge Wang, Wenbo Liang, Rong Xu, Jingchunyu Chen, Hui Song, Yue Fu, Jingxin Li, Chengjiang Gao, Mutian Jia, Chunyuan Zhao, Wei Zhao

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Figure 1

HERCs interact with NLRP3.

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HERCs interact with NLRP3.
(A) Identification of HERC6 as a potential NL...
(A) Identification of HERC6 as a potential NLRP3 interactor in LPS-stimulated mouse PMs by mass spectrometry. (B and C) Immunoblot analysis of HERC6 and ISG15 expression in LPS-stimulated (B) or mIL-1β–stimulated (C) mouse PMs. (D and E) RT-PCR analysis of Herc6 (D) or Isg15 (E) mRNA in LPS-stimulated or mIL-1β–stimulated mouse PMs. All data are presented as the mean ± SD. (F) Co-IP analysis of the association between mHERC6 and mNLRP3 in HEK293T cells transfected with the indicated plasmids. (G) Co-IP analysis of the association between hNLRP3 and hHERC5 or hHERC6 in HEK293T cells transfected with the indicated plasmids. (H) Co-IP analysis of the association between HERC5 and NLRP3, ASC, or CASP1 in HEK293T cells transfected with the indicated plasmids. (I) Myc-NLRP3 and Flag-HERC5 were obtained by in vitro transcription and translation. The interaction between NLRP3 and HERC5 was assayed by mixing recombinant Myc-NLRP3 and Flag-HERC5, followed by co-IP with Myc antibody and immunoblot analysis with Flag or Myc antibody. (J) Co-IP analysis of the endogenous association between HERC6 and NLRP3, ASC, CASP1, or NEK7 in LPS-stimulated or LPS-primed and ATP-activated mouse PMs. (K) Co-IP analysis of the endogenous association between HERC5 and NLRP3, ASC, CASP1, or NEK7 in LPS-stimulated or LPS-primed and ATP-activated THP-1 cells. (L) Co-IP analysis of the association between NLRP3 and HERC5, ARIH1, or TRIM25 in HEK293T cells transfected with the indicated plasmids. Similar results were obtained from 3 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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