Journal
CELL HOST & MICROBE
Volume 22, Issue 1, Pages 74-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2017.06.005
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Funding
- startup fund
- Brinson Foundation
- Cancer Research Foundation
- American Cancer Society [IRG-58-004-53-IRG]
- University of Chicago Digestive Diseases Research Core Center (NIDDK) [P30DK42086]
- University of Chicago Comprehensive Cancer Center Support Grant [P30 CA14599]
- Cancer Center Core facilities (DNA)
- National Center for Advancing Translational Sciences of the NIH [UL1 TR000430]
- NIH [T32 GM007183, T32 AI007090]
- NCI-NIH award [F31CA177194-01]
- VA grant [I01 BX002369]
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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.
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