Article | Published:

STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling

Nature Structural & Molecular Biology volume 24, pages 279289 (2017) | Download Citation

Abstract

Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn may interfere with medical interventions. The JAK–STAT signaling pathway transmits the IFN extracellular signal to the nucleus, thus resulting in alterations in gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized, crucial component of the USP18-mediated negative-feedback control in both human and mouse cells. We found that STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site. This mechanistic coupling of effector and negative-feedback functions of STAT2 may provide novel strategies for treatment of IFN-signaling-related human diseases.

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Acknowledgements

We thank A. Garcia-Sastre (Icahn School of Medicine at Mount Sinai) for Stat2−/− MEFs, D. Cheresh (Moores UCSD Cancer Center) for MDA-MB-231, G. Stark (Cleveland Clinic) for sharing U-series cell lines, S. Fujita (Ehime University School of Medicine) for KT-1 cells, R. Xiang (The Scripps Research Institute) for WEHI-3B cells, S. Urbe (University of Liverpool) for GFP-fusion STAT2 and USP18 constructs, V. Verkhusha (Albert Einstein College of Medicine) for the mTag-BFP construct, T. Akagi (KAN Research Institute) for providing pCX4-series vectors, S. Kotenko (Rutgers New Jersey Medical School) for the pcDEF-hIFNAR2 DNA construct, D. Baker (Biogen Idec) for supplying recombinant human IFNβ and anti–human IFNAR1 antibody, the staff of Hybrigenics for their contribution, G. Hikade for technical support, and R. Kurre for advice on fluorescence microscopy. This study was supported by NIH R01HL091549 and R01CA177305 to D.-E.Z. and SFB 944 from the DFG to J.P. and J.J.H.

Author information

Author notes

    • Frédéric Colland

    Present address: Institut de Recherche Servier, Croissy-sur-Seine, France.

    • Kei-ichiro Arimoto
    •  & Sara Löchte

    These authors contributed equally to this work.

Affiliations

  1. Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.

    • Kei-ichiro Arimoto
    • , Samuel A Stoner
    • , Christoph Burkart
    • , Sayuri Miyauchi
    • , Jun-Bao Fan
    • , Ming Yan
    •  & Dong-Er Zhang
  2. Department of Biology, University of Osnabrück, Osnabrück, Germany.

    • Sara Löchte
    • , Stephan Wilmes
    • , Jürgen J Heinisch
    •  & Jacob Piehler
  3. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.

    • Yue Zhang
    •  & Dong-Er Zhang
  4. Institut Pasteur, Cytokine Signaling Unit, Inserm, Paris, France.

    • Zhi Li
    •  & Sandra Pellegrini
  5. Hybrigenics, impasse Reille, Paris, France.

    • Frédéric Colland
  6. Department of Pathology, University of California San Diego, La Jolla, California, USA.

    • Dong-Er Zhang

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Contributions

K.A., S.L., and S.A.S. designed, performed, and analyzed experiments, and wrote the manuscript; C.B., Y.Z., S.M., J.-B.F., S.W., J.J.H., Z.L., M.Y., S.P., and F.C. performed experiments or provided critical information; J.P. and D.-E.Z. conceived the project, designed experiments, analyzed experimental data, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jacob Piehler or Dong-Er Zhang.

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DOI

https://doi.org/10.1038/nsmb.3378