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

  • Nat Struct Mol Biol. 2017 Mar;24(3):279-289. doi: 10.1038/nsmb.3378.
Kei-Ichiro Arimoto  1 ,  Sara Löchte  2 ,  Samuel A Stoner  1 ,  Christoph Burkart  1 ,  Yue Zhang  3 ,  Sayuri Miyauchi  1 ,  Stephan Wilmes  2 ,  Jun-Bao Fan  1 ,  Jürgen J Heinisch  2 ,  Zhi Li  4 ,  Ming Yan  1 ,  Sandra Pellegrini  4 ,  Frédéric Colland  5 ,  Jacob Piehler  2 ,  Dong-Er Zhang  1  3  6
Affiliations
  • 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.
PMID: 28165510 DOI: 10.1038/nsmb.3378
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.