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

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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Publication Details

Journal
Nature Communications
Published
2025-02-24
DOI
https://doi.org/10.1038/s41467-025-57245-3
Citations
4
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
3.22

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article

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

Shurui Liu, Yinming Liang, Birong Zheng, Miao He et al.
4 citations
Nature Communications
RNA modifications and cancer
3.22
article

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

Shurui Liu, Yinming Liang, Birong Zheng, Miao He, Panpan Hou, Deyin Guo, Liaoxun Lu, Junhai Chen, Yu Ye, Zixiao Yang, Lang Bu, L Z Xie, Yongheng Zhong, Jingshu Xiao, Chunmei Li, Rui Li, Penghui Jia, Zibo Li, Yuxin Lin
article en
4 citations

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.

Nature CommunicationsVol. 16(1)
Sun Yat-sen University (CN), Shenzhen University (CN), First Affiliated Hospital of Guangzhou Medical University (CN), State Key Laboratory of Respiratory Disease (CN), Henan Medical University (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China
Zero hunger
Openalex Percentile: Top 9%
RNA modifications and cancer
3.22
DOIOpen Access PDFOpenAlex
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