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.


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.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • DEAD Box Protein 58 / chemistry
  • DEAD Box Protein 58 / metabolism*
  • HEK293 Cells
  • Humans
  • Immunity, Innate / drug effects*
  • Interferon-Induced Helicase, IFIH1 / chemistry
  • Interferon-Induced Helicase, IFIH1 / metabolism*
  • Interleukin-6 / metabolism
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Sendai virus / physiology
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Vesiculovirus / physiology


  • Antiviral Agents
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Ubiquitin-Protein Ligases
  • Ddx58 protein, mouse
  • Ifih1 protein, mouse
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1