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Nat Struct Mol Biol. 2017 Mar;24(3):279-289. doi: 10.1038/nsmb.3378. Epub 2017 Feb 6.

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

Author information

1
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
2
Department of Biology, University of Osnabrück, Osnabrück, Germany.
3
Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.
4
Institut Pasteur, Cytokine Signaling Unit, Inserm, Paris, France.
5
Hybrigenics, impasse Reille, Paris, France.
6
Department of Pathology, University of California San Diego, La Jolla, California, USA.

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.

PMID:
28165510
PMCID:
PMC5365074
DOI:
10.1038/nsmb.3378
[Indexed for MEDLINE]
Free PMC Article

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