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

R. Blake Richardson, Maikke B. Ohlson, Jennifer L. Eitson, Ashwani Kumar, Matthew B. McDougal, Ian N. Boys, Katrina B. Mar, Pamela C. De La Cruz-Rivera, Connor Douglas, Genevieve Konopka, Chao Xing, John W. Schoggins

Research output: Contribution to journalLetterpeer-review

86 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1214-1223
Number of pages10
JournalNature microbiology
Issue number11
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology


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