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

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

Author information

1
Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA.
2
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
3
Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
4
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Biological Sciences Collegiate Division, University of Chicago, Chicago, IL 60637, USA.
7
Laboratory of Immunoparasitology, World Premier International Research Center Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
8
Departments of Medicine, Molecular Genetics and Microbiology, and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
9
Departments of Medicine, Molecular Genetics and Microbiology, and Immunology, Duke University Medical Center, Durham, NC 27710, USA; GRECC, Durham VA Health Care System, Durham, NC 27705, USA.
10
Committee on Microbiology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. Electronic address: shwang@bsd.uchicago.edu.

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

PMID:
28669671
PMCID:
PMC5591033
DOI:
10.1016/j.chom.2017.06.005
[Indexed for MEDLINE]
Free PMC Article

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