2. Academic Validation
  3. The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I

The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I

  • Cell Rep. 2017 Nov 7;21(6):1613-1623. doi: 10.1016/j.celrep.2017.10.020.
Chunyuan Zhao 1,  Mutian Jia 2,  Hui Song 2,  Zhongxia Yu 2,  Wenwen Wang 2,  Qi Li 2,  Lining Zhang 3,  Wei Zhao 4,  Xuetao Cao 5
Affiliations

Affiliations

  • 1 Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
  • 2 Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong 250012, China; State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250012, China.
  • 3 Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong 250012, China.
  • 4 Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong 250012, China; State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250012, China. Electronic address: wzhao@sdu.edu.cn.
  • 5 Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China. Electronic address: caoxt@immunol.org.
PMID: 29117565 DOI: 10.1016/j.celrep.2017.10.020
Abstract

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5) and RIG-I, are crucial for host recognition of non-self RNAs, especially viral RNA. Thus, the expression and activation of RLRs play fundamental roles in eliminating the invading RNA viruses and maintaining immune homeostasis. However, how RLR expression is tightly regulated remains to be further investigated. In this study, we identified a major histocompatibility complex (MHC)-encoded gene, tripartite interaction motif 40 (TRIM40), as a suppressor of RLR signaling by directly targeting MDA5 and RIG-I. TRIM40 binds to MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination via its E3 Ligase activity, leading to their proteasomal degradation. TRIM40 deficiency enhances RLR-triggered signaling. Consequently, TRIM40 deficiency greatly enhances Antiviral immune responses and decreases viral replication in vivo. Thus, we demonstrate that TRIM40 limits RLR-triggered innate activation, suggesting TRIM40 as a potential therapeutic target for the control of viral Infection.

Keywords

MDA5; RIG-I; TRIM40; innate immunity; type I interferon.

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