Ubiquitination of NLRP3 by gp78/Insig-1 restrains NLRP3 inflammasome activation

  • Cell Death Differ. 2022 Aug;29(8):1582-1595. doi: 10.1038/s41418-022-00947-8.
Ting Xu   #  1 ,  Weiwei Yu   #  1 ,  Hui Fang   #  1 ,  Zhen Wang  1 ,  Zhexu Chi  1 ,  Xingchen Guo  2 ,  Danlu Jiang  1 ,  Kailian Zhang  1 ,  Sheng Chen  1 ,  Mobai Li  1 ,  Yuxian Guo  1 ,  Jian Zhang  1 ,  Dehang Yang  1 ,  Qianzhou Yu  1 ,  Di Wang  3  4 ,  Xue Zhang  5
Affiliations
  • 1. Institute of Immunology and Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China.
  • 2. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, 430072, Wuhan, P.R. China.
  • 3. Institute of Immunology and Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China. [email protected].
  • 4. Liangzhu Laboratory, Zhejiang University Medical Center, 311121, Hangzhou, P.R. China. [email protected].
  • 5. Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, P.R. China. [email protected].
  • # Contributed equally.
PMID: 35110683 DOI: 10.1038/s41418-022-00947-8
Abstract

The NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome plays a pivotal role in defending the host against Infection as well as sterile inflammation. Activation of the NLRP3 inflammasome is critically regulated by a de-ubiquitination mechanism, but little is known about how ubiquitination restrains NLRP3 activity. Here, we showed that the membrane-bound E3 ubiquitin Ligase gp78 mediated mixed ubiquitination of NLRP3, which inhibited NLRP3 inflammasome activation by suppressing the oligomerization and subcellular translocation of NLRP3. In addition, the endoplasmic reticulum membrane protein insulin-induced gene 1 (Insig-1) was required for this gp78-NLRP3 interaction and gp78-mediated NLRP3 ubiquitination. gp78 or Insig-1 deficiency in myeloid cells led to exacerbated NLRP3 inflammasome-dependent inflammation in vivo, including lipopolysaccharide-induced systemic inflammation and alum-induced Peritonitis. Taken together, our study identifies gp78-mediated NLRP3 ubiquitination as a regulatory mechanism that restrains inflammasome activation and highlights NLRP3 ubiquitination as a potential therapeutic target for inflammatory diseases.

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