STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling.
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.
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
Kei-Ichiro
KI
Arimoto
Department of Biology, University of Osnabrück, Osnabrück, Germany.
Sara
S
Löchte
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
Samuel A
SA
Stoner
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
Christoph
C
Burkart
Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.
Yue
Y
Zhang
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
Sayuri
S
Miyauchi
Department of Biology, University of Osnabrück, Osnabrück, Germany.
Stephan
S
Wilmes
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
Jun-Bao
JB
Fan
Department of Biology, University of Osnabrück, Osnabrück, Germany.
Jürgen J
JJ
Heinisch
Institut Pasteur, Cytokine Signaling Unit, Inserm, Paris, France.
Zhi
Z
Li
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
Ming
M
Yan
Institut Pasteur, Cytokine Signaling Unit, Inserm, Paris, France.
Sandra
S
Pellegrini
Hybrigenics, impasse Reille, Paris, France.
Frédéric
F
Colland
Department of Biology, University of Osnabrück, Osnabrück, Germany.
Jacob
J
Piehler
Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.|Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.|Department of Pathology, University of California San Diego, La Jolla, California, USA.
Dong-Er
DE
Zhang
D000818:Animals; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D015151:Immunoblotting; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D043222:Ubiquitin Thiolesterase
C508033:IFNAR2 protein, human; D007370:Interferon Type I; D050505:Mutant Proteins; D050795:STAT2 Transcription Factor; D053633:Receptor, Interferon alpha-beta; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase