Assembly of the WHIP-TRIM14-PPP6C Mitochondrial Complex Promotes RIG-I-Mediated Antiviral Signaling

Mol Cell. 2017 Oct 19;68(2):293-307.e5. doi: 10.1016/j.molcel.2017.09.035.

Abstract

Mitochondrial antiviral signaling platform protein (MAVS) acts as a central hub for RIG-I receptor proximal signal propagation. However, key components in the assembly of the MAVS mitochondrial platform that promote RIG-I mitochondrial localization and optimal activation are still largely undefined. Employing pooled RNAi and yeast two-hybrid screenings, we report that the mitochondrial adaptor protein tripartite motif (TRIM)14 provides a docking platform for the assembly of the mitochondrial signaling complex required for maximal activation of RIG-I-mediated signaling, consisting of WHIP and protein phosphatase PPP6C. Following viral infection, the ubiquitin-binding domain in WHIP bridges RIG-I with MAVS by binding to polyUb chains of RIG-I at lysine 164. The ATPase domain in WHIP contributes to stabilization of the RIG-I-dsRNA interaction. Moreover, phosphatase PPP6C is responsible for RIG-I dephosphorylation. Together, our findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated innate antiviral immunity.

Keywords: ATPase domain; K63 ubiquitination; RIG-I-like receptor signaling; dephosphorylation; mitochondrial signalosome; ubiquitin binding.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / immunology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Humans
  • Immunity, Innate*
  • Intracellular Signaling Peptides and Proteins
  • Mitochondria / genetics
  • Mitochondria / immunology*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / immunology*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / immunology*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Tripartite Motif Proteins
  • Vero Cells
  • Virus Diseases / genetics
  • Virus Diseases / immunology
  • Viruses / genetics
  • Viruses / immunology

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • TRIM14 protein, human
  • Tripartite Motif Proteins
  • Phosphoprotein Phosphatases
  • protein phosphatase 6
  • DDX58 protein, human
  • WRNIP1 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • DEAD Box Protein 58