Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation.

Jun 24, 2021

Contributor: Yong Shen,Kejun Tang,Dongdong Chen,Mengying Hong,Fangfang Sun,SaiSai Wang,Yuehai Ke,Tingting Wu,Ren Sun,Jing Qian,Yushen Du

Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation.

The type I interferon (IFN) pathway is a key component of innate immune response upon invasion of foreign pathogens. It is also under precise control to prevent excessive upregulation and undesired inflammation cascade. In the present study, we report that Riok3, an atypical kinase, negatively regulates retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) sensing-induced type I IFN signaling. Riok3 deficiency selectively inhibits RNA viral replication in vitro, resulting from an upregulated type I IFN pathway. Mice with myeloid-specific Riok3 knockout also show a more robust induction of type I IFN upon RNA virus infection and are more resistant to RNA virus-induced pathogenesis. Mechanistically, Riok3 recruits and interacts with the E3 ubiquitin ligase TRIM40, leading to the degradation of RIG-I and melanoma differentiation-associated gene-5 (MDA5) via K48- and K27-linked ubiquitination. Collectively, our data reveal the mechanism that Riok3 employs to be a negative regulator of antiviral innate immunity.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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About The Expert

Yong Shen

Cancer Institute, ZJU-UCLA Joint Center for Medical Education and Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China; Department of Breast Surgery, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, P.R. China.

Kejun Tang

Cancer Institute, ZJU-UCLA Joint Center for Medical Education and Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China; Department of Surgery, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R. China.

Dongdong Chen

Cancer Institute, ZJU-UCLA Joint Center for Medical Education and Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.

Mengying Hong

Cancer Institute, ZJU-UCLA Joint Center for Medical Education and Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.

Fangfang Sun

Cancer Institute, ZJU-UCLA Joint Center for Medical Education and Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.

SaiSai Wang

Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China.

Yuehai Ke

Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.

Tingting Wu

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Ren Sun

Cancer Institute, ZJU-UCLA Joint Center for Medical Education and Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; School of Biomedical Sciences, LKS Faculty of Medicine, The Hongkong University, Hongkong, China. Electronic address: rensun@hku.hk.

Jing Qian

Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China. Electronic address: jingqian@zju.edu.cn.

Yushen Du

Cancer Institute, ZJU-UCLA Joint Center for Medical Education and Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R. China; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: lilyduyushen@zju.edu.cn.

References

PubMed