2. Academic Validation
  3. RNF167 mediates atypical ubiquitylation and degradation of RLRs via two distinct proteolytic pathways

RNF167 mediates atypical ubiquitylation and degradation of RLRs via two distinct proteolytic pathways

  • Nat Commun. 2025 Feb 24;16(1):1920. doi: 10.1038/s41467-025-57245-3.
Miao He 1 2 3,  Zixiao Yang 3,  Luyang Xie 3,  Junhai Chen 3,  Shurui Liu 1 2 4,  Liaoxun Lu 5,  Zibo Li 3,  Birong Zheng 1 2 4,  Yu Ye 3,  Yuxin Lin 2,  Lang Bu 3,  Jingshu Xiao 3,  Yongheng Zhong 3,  Penghui Jia 3,  Qiang Li 3,  Yinming Liang 5,  Deyin Guo 1 2 4,  Chun-Mei Li 6,  Panpan Hou 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China.
  • 2 Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China.
  • 3 MOE Key Laboratory of Tropical Disease Control, Centre for Infection and Immunity Studies, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, China.
  • 4 Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 5 Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003, China.
  • 6 MOE Key Laboratory of Tropical Disease Control, Centre for Infection and Immunity Studies, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, China. lichm8@mail.sysu.edu.cn.
  • 7 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China. houpp@mail.sysu.edu.cn.
PMID: 39994288 DOI: 10.1038/s41467-025-57245-3
Abstract

The precise regulation of the RIG-I-like receptors (RLRs)-mediated type I interferon (IFN-I) activation is crucial in Antiviral immunity and maintaining host immune homeostasis in the meantime. Here, we identify an E3 ubiquitin Ligase, namely RNF167, as a negative regulator of RLR-triggered IFN signaling. Mechanistically, RNF167 facilitates both atypical K6- and K11-linked polyubiquitination of RIG-I/MDA5 within CARD and CTD domains, respectively, which leads to degradation of the viral RNA sensors through dual proteolytic pathways. RIG-I/MDA5 conjugated with K6-linked ubiquitin chains in CARD domains is recognized by the Autophagy cargo adaptor p62, that delivers the substrates to autolysosomes for selective autophagic degradation. In contrast, K11-linked polyubiquitination in CTD domains leads to proteasome-dependent degradation of RLRs. Thus, our study clarifies a function of atypical K6- and K11-linked polyubiquitination in the regulation of RLR signaling. We also unveil an elaborate synergistic effect of dual proteolysis systems to control amplitude and duration of IFN-I activation, hereby providing insights into physiological roles of the cross-talk between these two protein quality control pathways.

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