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Nat Microbiol. 2018 Nov;3(11):1214-1223. doi: 10.1038/s41564-018-0244-1. Epub 2018 Sep 17.

A CRISPR screen identifies IFI6 as an ER-resident interferon effector that blocks flavivirus replication.

Author information

1
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Bioinformatics Core, McDermott Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
4
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. john.schoggins@utsouthwestern.edu.

Abstract

The endoplasmic reticulum (ER) is an architecturally diverse organelle that serves as a membrane source for the replication of multiple viruses. Flaviviruses, including yellow fever virus, West Nile virus, dengue virus and Zika virus, induce unique single-membrane ER invaginations that house the viral replication machinery1. Whether this virus-induced ER remodelling is vulnerable to antiviral pathways is unknown. Here, we show that flavivirus replication at the ER is targeted by the interferon (IFN) response. Through genome-scale CRISPR screening, we uncovered an antiviral mechanism mediated by a functional gene pairing between IFI6 (encoding IFN-α-inducible protein 6), an IFN-stimulated gene cloned over 30 years ago2, and HSPA5, which encodes the ER-resident heat shock protein 70 chaperone BiP. We reveal that IFI6 is an ER-localized integral membrane effector that is stabilized through interactions with BiP. Mechanistically, IFI6 prophylactically protects uninfected cells by preventing the formation of virus-induced ER membrane invaginations. Notably, IFI6 has little effect on other mammalian RNA viruses, including the related Flaviviridae family member hepatitis C virus, which replicates in double-membrane vesicles that protrude outwards from the ER. These findings support a model in which the IFN response is armed with a membrane-targeted effector that discriminately blocks the establishment of virus-specific ER microenvironments that are required for replication.

PMID:
30224801
PMCID:
PMC6202210
[Available on 2019-03-17]
DOI:
10.1038/s41564-018-0244-1

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