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GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses

Nature Immunology volume 15, pages 6371 (2014) | Download Citation

Abstract

Detailed understanding of the signaling intermediates that confer the sensing of intracellular viral nucleic acids for induction of type I interferons is critical for strategies to curtail viral mechanisms that impede innate immune defenses. Here we show that the activation of the microtubule-associated guanine nucleotide exchange factor GEF-H1, encoded by Arhgef2, is essential for sensing of foreign RNA by RIG-I–like receptors. Activation of GEF-H1 controls RIG-I–dependent and Mda5-dependent phosphorylation of IRF3 and induction of IFN-β expression in macrophages. Generation of Arhgef2−/− mice revealed a pronounced signaling defect that prevented antiviral host responses to encephalomyocarditis virus and influenza A virus. Microtubule networks sequester GEF-H1 that upon activation is released to enable antiviral signaling by intracellular nucleic acid detection pathways.

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Acknowledgements

This work was supported by grants AI-093588 (H.-C.R.), DK-068181 (H.-C.R.), DK-033506 (H.-C.R.), DK-043351 (H.-C.R. and C.T.) and DK-52510 (C.T.) from the US National Institutes of Health.

Author information

Author notes

    • Hao-Sen Chiang
    •  & Yun Zhao

    These authors contributed equally to this work.

Affiliations

  1. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Hao-Sen Chiang
    • , Yun Zhao
    • , Joo-Hye Song
    • , Song Liu
    • , Megha Basavappa
    • , Kate L Jeffrey
    •  & Hans-Christian Reinecker
  2. Division of Immunology, Beth Israel Deaconess Medical Center and Center for the Study of Inflammatory Bowel Disease, Harvard Medical School, Boston, Massachusetts, USA.

    • Ninghai Wang
    •  & Cox Terhorst
  3. Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Arlene H Sharpe

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Contributions

H.-S.C., Y.Z., J.-H.S., S.L., N.W. and M.B. carried out experiments; K.J., A.H.S. and C.T. supported the development of research tools and mice; K.L.J. provided virus and advised on virus infection experiments; H.-C.R. conceived of and directed all research, and along with H.-S.C. prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hans-Christian Reinecker.

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DOI

https://doi.org/10.1038/ni.2766

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