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

Miao He, Zixiao Yang, Luyang Xie, Junhai Chen, Shurui Liu, Liaoxun Lu, Zibo Li, Birong Zheng, Yu Ye, Yuxin Lin, Lang Bu, Jingshu Xiao, Yongheng Zhong, Penghui Jia, Qiang Li, Yinming Liang, Deyin Guo, Chun-Mei Li () and Panpan Hou ()
Additional contact information
Miao He: the First Affiliated Hospital of Guangzhou Medical University
Zixiao Yang: Shenzhen Campus of Sun Yat-sen University
Luyang Xie: Shenzhen Campus of Sun Yat-sen University
Junhai Chen: Shenzhen Campus of Sun Yat-sen University
Shurui Liu: the First Affiliated Hospital of Guangzhou Medical University
Liaoxun Lu: Xinxiang Medical University
Zibo Li: Shenzhen Campus of Sun Yat-sen University
Birong Zheng: the First Affiliated Hospital of Guangzhou Medical University
Yu Ye: Shenzhen Campus of Sun Yat-sen University
Yuxin Lin: Guangzhou International Bio-Island
Lang Bu: Shenzhen Campus of Sun Yat-sen University
Jingshu Xiao: Shenzhen Campus of Sun Yat-sen University
Yongheng Zhong: Shenzhen Campus of Sun Yat-sen University
Penghui Jia: Shenzhen Campus of Sun Yat-sen University
Qiang Li: Shenzhen Campus of Sun Yat-sen University
Yinming Liang: Xinxiang Medical University
Deyin Guo: the First Affiliated Hospital of Guangzhou Medical University
Chun-Mei Li: Shenzhen Campus of Sun Yat-sen University
Panpan Hou: the First Affiliated Hospital of Guangzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57245-3

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