The Zinc-Finger Protein ZCCHC3 Binds RNA and Facilitates Viral RNA Sensing and Activation of the RIG-I-like Receptors

Immunity. 2018 Sep 18;49(3):438-448.e5. doi: 10.1016/j.immuni.2018.08.014. Epub 2018 Sep 4.

Abstract

Recognition of viral RNA by the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiates innate antiviral immune response. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified ZCCHC3 as a positive regulator of the RLRs including RIG-I and MDA5. ZCCHC3 deficiency markedly inhibited RNA virus-triggered induction of downstream antiviral genes, and ZCCHC3-deficient mice were more susceptible to RNA virus infection. ZCCHC3 was associated with RIG-I and MDA5 and functions in two distinct processes for regulation of RIG-I and MDA5 activities. ZCCHC3 bound to dsRNA and enhanced the binding of RIG-I and MDA5 to dsRNA. ZCCHC3 also recruited the E3 ubiquitin ligase TRIM25 to the RIG-I and MDA5 complexes to facilitate its K63-linked polyubiquitination and activation. Thus, ZCCHC3 is a co-receptor for RIG-I and MDA5, which is critical for RLR-mediated innate immune response to RNA virus.

Keywords: RIG-I-like receptors; RNA virus; ZCCHC3; co-receptor; innate antiviral response; polyubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • DEAD Box Protein 58 / metabolism*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Viral
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Interferon-Induced Helicase, IFIH1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • RNA Virus Infections / immunology*
  • RNA Viruses / physiology*
  • RNA, Viral / immunology
  • RNA, Viral / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • THP-1 Cells
  • Transcription Factors / metabolism
  • Ubiquitination

Substances

  • DNA-Binding Proteins
  • RNA, Viral
  • RNA-Binding Proteins
  • Transcription Factors
  • Trim25 protein, mouse
  • ZCCHC3 protein, mouse
  • Ifih1 protein, mouse
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1