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

doi:10.1016/j.chom.2017.06.005

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 journal › Article › peer-review

70 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 language	English (US)
Pages (from-to)	74-85.e7
Journal	Cell Host and Microbe
Volume	22
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2017.06.005
State	Published - Jul 12 2017
Externally published	Yes

Keywords

GBP
GTPase
IRG
LC3
RNA
autophagy
interferon
replication
targeting
virus

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2017.06.005

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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

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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.",

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author = "Biering, {Scott B.} and Jayoung Choi and Halstrom, {Rachel A.} and Brown, {Hailey M.} and Beatty, {Wandy L.} and Sanghyun Lee and McCune, {Broc T.} and Erin Dominici and Williams, {Lelia E.} and Orchard, {Robert C.} and Wilen, {Craig B.} and Masahiro Yamamoto and J{\"o}rn Coers and Taylor, {Gregory A.} and Seungmin Hwang",

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AU - Choi, Jayoung

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AU - Brown, Hailey M.

AU - Beatty, Wandy L.

AU - Lee, Sanghyun

AU - McCune, Broc T.

AU - Dominici, Erin

AU - Williams, Lelia E.

AU - Orchard, Robert C.

AU - Wilen, Craig B.

AU - Yamamoto, Masahiro

AU - Coers, Jörn

AU - Taylor, Gregory A.

AU - Hwang, Seungmin

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N2 - 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.

AB - 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.

KW - GBP

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KW - IRG

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KW - autophagy

KW - interferon

KW - replication

KW - targeting

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

Abstract

Keywords

ASJC Scopus subject areas

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