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E3 ubiquitin ligase RNF170 inhibits innate immune responses by targeting and degrading TLR3 in murine cells

Cellular & Molecular Immunology (2019) | Download Citation

Abstract

Upon recognition of dsRNA, toll-like receptor 3 (TLR3) recruits the adaptor protein TRIF to activate IRF3 and NF-κB signaling, initiating innate immune responses. The ubiquitination of TLR3 downstream signaling molecules and their roles in the innate response have been discovered; however, whether TLR3 itself is ubiquitinated and then functionally involved remains to be elucidated. By immunoprecipitating TLR3-binding proteins in macrophages, we identified ring finger protein 170 (RNF170) as a TLR3-binding E3 ligase. RNF170 mediated the K48-linked polyubiquitination of K766 in the TIR domain of TLR3 and promoted the degradation of TLR3 through the proteasome pathway. The genetic ablation of RNF170 selectively augmented TLR3-triggered innate immune responses both in vitro and in vivo. Our results reveal a novel role for RNF170 in selectively inhibiting TLR3-triggered innate immune responses by promoting TLR3 degradation.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant 81788101 to X.C.; grant 81871236 to M.J.), the National 135 Mega Program of China (grant 2017ZX10202203-002 to M.J.; grant 2017ZX10203206-001 to X.C.), the CAMS Innovation Fund for Medical Sciences (grant 2016-12M-1-003 to X.C.) and the Medical Epigenetics Research Center, Chinese Academy of Medical Sciences (2018PT31015).

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Affiliations

  1. National Key Laboratory of Medical Molecular Biology, Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China

    • Xiaoqi Song
    • , Shuo Liu
    • , Wendie Wang
    • , Zhongfei Ma
    • , Xuetao Cao
    •  & Minghong Jiang
  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 200433, Shanghai, China

    • Xuetao Cao
  3. School of Medicine, Nankai University, 300071, Tianjin, China

    • Xuetao Cao

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Contributions

M.J. and X.C. designed the research; X.S., M.J., S.L., W.W. and Z.M. performed the experiments; and X.S., M.J. and X.C. analyzed the data and wrote the paper.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Minghong Jiang.

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DOI

https://doi.org/10.1038/s41423-019-0236-y