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

Scott B. Biering, Jayoung Choi, Rachel A. Halstrom, Hailey M. Brown, Wandy L. Beatty, Sanghyun Lee, Broc T. McCune, Erin Dominici, Lelia E. Williams, Robert C. Orchard, Craig B. Wilen, Masahiro Yamamoto, Jörn Coers, Gregory A. Taylor, Seungmin Hwang

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)74-85.e7
JournalCell Host and Microbe
Volume22
Issue number1
DOIs
StatePublished - Jul 12 2017
Externally publishedYes

Keywords

  • GBP
  • GTPase
  • IRG
  • LC3
  • RNA
  • autophagy
  • interferon
  • replication
  • targeting
  • virus

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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    Biering, S. B., Choi, J., Halstrom, R. A., Brown, H. M., Beatty, W. L., Lee, S., McCune, B. T., Dominici, E., Williams, L. E., Orchard, R. C., Wilen, C. B., Yamamoto, M., Coers, J., Taylor, G. A., & Hwang, S. (2017). Viral Replication Complexes Are Targeted by LC3-Guided Interferon-Inducible GTPases. Cell Host and Microbe, 22(1), 74-85.e7. https://doi.org/10.1016/j.chom.2017.06.005