Viral Replication Complexes Are Targeted by LC3-Guided Interferon-Inducible GTPases

Cell Host Microbe. 2017 Jul 12;22(1):74-85.e7. doi: 10.1016/j.chom.2017.06.005. Epub 2017 Jun 29.

Abstract

All viruses with positive-sense RNA genomes replicate on membranous structures in the cytoplasm called replication complexes (RCs). RCs provide an advantageous microenvironment for viral replication, but it is unknown how the host immune system counteracts these structures. Here we show that interferon-gamma (IFNG) disrupts the RC of murine norovirus (MNV) via evolutionarily conserved autophagy proteins and the induction of IFN-inducible GTPases, which are known to destroy the membrane of vacuoles containing bacteria, protists, or fungi. The MNV RC was marked by the microtubule-associated-protein-1-light-chain-3 (LC3) conjugation system of autophagy and then targeted by immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs) upon their induction by IFNG. Further, the LC3 conjugation system and the IFN-inducible GTPases were necessary to inhibit MNV replication in mice and human cells. These data suggest that viral RCs can be marked and antagonized by a universal immune defense mechanism targeting diverse pathogens replicating in cytosolic membrane structures.

Keywords: GBP; GTPase; IRG; LC3; RNA; autophagy; interferon; replication; targeting; virus.

MeSH terms

  • Animals
  • Autophagy
  • Caliciviridae Infections / virology
  • Carrier Proteins / metabolism
  • Cell Line
  • Cytosol
  • Female
  • Fibroblasts
  • GTP Phosphohydrolases / immunology
  • GTP Phosphohydrolases / metabolism*
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Immunity, Innate
  • Interferon-gamma / metabolism
  • Interferons / metabolism*
  • Interferons / pharmacology
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / immunology
  • Microtubule-Associated Proteins / metabolism*
  • Norovirus / genetics*
  • Norovirus / immunology
  • Norovirus / pathogenicity
  • Norovirus / physiology*
  • RAW 264.7 Cells
  • Vacuoles / microbiology
  • Viral Plaque Assay
  • Virus Replication / drug effects*

Substances

  • Carrier Proteins
  • MAP1LC3 protein, mouse
  • Microtubule-Associated Proteins
  • Interferon-gamma
  • Interferons
  • GTP Phosphohydrolases