A non-canonical role of the p97 complex in RIG-I antiviral signaling

EMBO J. 2015 Dec 2;34(23):2903-20. doi: 10.15252/embj.201591888. Epub 2015 Oct 15.

Abstract

RIG-I is a well-studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. Viral infection significantly strengthens the interaction between RIG-I and the p97 complex by a conformational change of RIG-I that exposes the CARDs and through K63-linked ubiquitination of these CARDs. Disruption of the p97 complex enhances RIG-I antiviral signaling. Consistently, administration of compounds targeting p97 ATPase activity was shown to inhibit viral replication and protect mice from vesicular stomatitis virus (VSV) infection. Overall, our study uncovered a previously unrecognized role for the p97 complex in protein ubiquitination and revealed the p97 complex as a potential drug target in antiviral therapy.

Keywords: RIG‐I; antiviral signaling; mechanism; p97‐Npl4; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Cell Line
  • HeLa Cells
  • Humans
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Signal Transduction*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / physiology
  • Vesicular Stomatitis / metabolism
  • Vesicular Stomatitis / prevention & control
  • Virus Replication / physiology

Substances

  • Nuclear Proteins
  • PLAAT4 protein, human
  • Receptors, Retinoic Acid
  • RNF125 protein, mouse
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • Adenosine Triphosphatases
  • p97 ATPase

Associated data

  • PDB/4RV0