title: Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon alpha receptor (IFNAR1)-associated tyrosine kinase Tyk2.
abstract: Type I IFNs are critical players in host innate and adaptive immunity. IFN signaling is tightly controlled to ensure appropriate immune responses as imbalance could result in uncontrolled inflammation or inadequate responses to infection. It is therefore important to understand how type I IFN signaling is regulated. Here we have investigated the mechanism by which suppressor of cytokine signaling 1 (SOCS1) inhibits type I IFN signaling. We have found that SOCS1 inhibits type I IFN signaling not via a direct interaction with the IFN α receptor 1 (IFNAR1) receptor component but through an interaction with the IFNAR1-associated kinase Tyk2. We have characterized the residues/regions involved in the interaction between SOCS1 and Tyk2 and found that SOCS1 associates via its SH2 domain with conserved phosphotyrosines 1054 and 1055 of Tyk2. The kinase inhibitory region of SOCS1 is also essential for its interaction with Tyk2 and inhibition of IFN signaling. We also found that Tyk2 is preferentially Lys-63 polyubiquitinated and that this activation reaction is inhibited by SOCS1. The consequent effect of SOCS1 inhibition of Tyk2 not only results in a reduced IFN response because of inhibition of Tyk2 kinase-mediated STAT signaling but also negatively impacts IFNAR1 surface expression, which is stabilized by Tyk2.
authors.affiliation: Centre for Innate Immunity and Infectious Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Rebecca A R
authors.initials: RA
authors.lastname: Piganis
authors.forename: Nicole A
authors.initials: NA
authors.lastname: De Weerd
authors.forename: Jodee A
authors.initials: JA
authors.lastname: Gould
authors.forename: Christian W
authors.initials: CW
authors.lastname: Schindler
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
mesh_terms: D000818:Animals; D004795:Enzyme Stability / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology; D018909:src Homology Domains
chemical_list: C507964:IFNAR1 protein, human; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053633:Receptor, Interferon alpha-beta; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse