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.
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The data sets generated and/or analysed during the current study are available from the corresponding author upon request.
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We thank N. Alto and J. Pfeiffer for critical manuscript feedback, M. Diamond and M. Henne for helpful discussions and C. Rice for reagents. We acknowledge the technical support of the UT Southwestern Live Cell Imaging Core and Electron Microscopy Core. This work was supported in part by NIH grants AI117922 and DK095031 (J.W.S.), the UT Southwestern Endowed Scholars program (J.W.S.), the Rita Allen Foundation (J.W.S.), the Clayton Foundation for Research (J.W.S.) and the National Science Foundation Graduate Research Fellowship Program grant 2016217834 (I.N.B.). C.X. was partially supported by NIH grant UL1TR001105. Additional support for R.B.R. and K.B.M. was obtained from NIH T32 Training grants AI007520 and AI005284, respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the other funders.
The authors declare no competing interests.
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