title: Nuclear transit of the intracellular domain of the interferon receptor subunit IFNaR2 requires Stat2 and Irf9.
abstract: Regulated intramembrane proteolysis (RIP) is the primary signaling mechanism for some receptors, such as Notch and the amyloid precursor protein. In addition, some receptor type tyrosine kinases, such as HER4, are able to signal via both kinase activation and regulated receptor proteolysis. Previously, we showed that the IFNaR2 subunit of the type I interferon receptor can be cleaved in a two step process that resembles RIP and that the IFNaR2 intracellular domain (IFNaR2-ICD) can mediate gene transcription in a Stat2 dependent manner. Here, we demonstrate that IFNaR2-ICD, Stat2 and Irf9 form a ternary complex. Furthermore, Stat2 and Irf9 are required for the nuclear transit of a GFP-linked IFNaR2-ICD construct (GFP-ICD). Additional experiments monitoring the nuclear localization of GFP-ICD demonstrate that Stat2 serves an adaptor role, mediating the interaction between the IFNaR2-ICD and Irf9, while the bipartite nuclear localization signal within Irf9 is the primary determinant driving nuclear transit of the ICD containing complex. Overall, the data suggest that liberation of the IFNaR2-ICD by regulated proteolysis could trigger a novel mechanism for moving the transcription factor Stat2 to the nucleus.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of California, IRVINE, Irvine, CA 92679, United States.
authors.forename: Ashraf
authors.initials: A
authors.lastname: El Fiky
authors.forename: Pete
authors.initials: P
authors.lastname: Pioli
authors.forename: Arif
authors.initials: A
authors.lastname: Azam
authors.forename: Kiwon
authors.initials: K
authors.lastname: Yoo
authors.forename: Kent L
authors.initials: KL
authors.lastname: Nastiuk
authors.forename: John J
authors.initials: JJ
authors.lastname: Krolewski
mesh_terms: D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000737:chemistry / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D019913:Nuclear Localization Signals / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053633:Receptor, Interferon alpha-beta / Q000737:chemistry*; D050795:STAT2 Transcription Factor / Q000737:chemistry / Q000378:metabolism*
chemical_list: C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D019913:Nuclear Localization Signals; D050795:STAT2 Transcription Factor; D053633:Receptor, Interferon alpha-beta