2. Academic Validation
  3. USP13 stabilizes NLRP3 to facilitate inflammasome activation by preventing TRIM31-mediated NLRP3 ubiquitination and degradation

USP13 stabilizes NLRP3 to facilitate inflammasome activation by preventing TRIM31-mediated NLRP3 ubiquitination and degradation

  • Sci Adv. 2025 Sep 26;11(39):eadx3827. doi: 10.1126/sciadv.adx3827.
Ya-Ting Li 1 2,  Ke-Ying Li 3 4,  Shou-Song Tao 5,  Ting Wang 1 2,  Ying Lu 1 2,  Hui Chen 2,  Yi-Qun Zhan 2,  Ke Zhao 2,  Shen-Si Xiang 2,  Jing-Jing Li 2,  Hui-Ying Gao 2,  Miao Yu 2,  Chang-Yan Li 2,  Lin Wang 1,  Xiao-Ming Yang 1 2,  Guang-Ming Ren 2,  Rong-Hua Yin 2
Affiliations

Affiliations

  • 1 Faculty of Chemistry and Life Sciences, Beijing University of Technology, Beijing 100124, China.
  • 2 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Radiation Medicine, Beijing 100850, China.
  • 3 Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China.
  • 4 Department of Blood Transfusion, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu 610000, Sichuan Province, China.
  • 5 Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
PMID: 41004574 DOI: 10.1126/sciadv.adx3827
Abstract

NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) has a fundamental role in host defense and is involved in diverse inflammatory diseases. NLRP3 protein expression is tightly controlled by the ubiquitin system. In particular, NLRP3 protein degradation has been extensively studied. In contrast, the mechanisms to stabilize NLRP3 protein are much less known. Here, we demonstrated the critical role of Ubiquitin-Specific Protease 13 (USP13) in regulating NLRP3 protein stability and inflammasome activation independently of its deubiquitinating enzyme activity. USP13 competes with E3 ubiquitin Ligase TRIM31 to interact with NLRP3 and prevents TRIM31-mediated NLRP3 ubiquitination at K192 and K496 sites, thereby inhibiting proteasomal degradation of NLRP3. USP13 deficiency reduces NLRP3 protein expression in both human and mouse macrophages, which consequently inhibits NLRP3 inflammasome assembly and activation. Accordingly, deficiency of USP13 attenuates monosodium urate crystal-induced mouse peritonitis. Overall, our findings reveal a previously unrecognized regulatory mechanism of NLRP3 stability by USP13 and provide a potential therapeutic target for NLRP3-driven diseases.

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