1. Academic Validation
  2. 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.
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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