Characterisation of suppressor of cytokine signaling 1 regulation of type I interferon signaling
Creators: name: Piganis, Rebecca
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Type I Interferons (IFNs) are critical players in host innate and adaptive immunity. IFN signaling is tightly controlled to ensure an appropriate immune response is generated, as an imbalance could result in uncontrolled inflammation or inadequate responses to infection. It is therefore important to understand the signaling events activated in the cell following type I IFN stimulation and how signaling is regulated. SOCS1 is a negative regulator of type I IFN signaling, acting in a negative feedback loop. This thesis details the mechanism of SOCS1 regulation of type I IFN signaling as well as the consequences of this regulation in terms of its effect on IFNα induced STAT activation and the resultant transcriptional response. Results in this thesis demonstrate that SOCS1 inhibits type I IFN signaling through an interaction with the type I IFN receptor (IFNAR1) associated kinase, TYK2. SOCS1 associates via its SH2 domain with conserved phospho-tyrosines 1054 and 1055 of TYK2 as well with the kinase inhibitor region (KIR). TYK2 is preferentially Lys-63 polyubiquitinated and this activation reaction is inhibited by SOCS1. The consequent effect of SOCS1 inhibition of TYK2 not only results in a reduced IFN response due to inhibition of TYK2 kinase mediated STAT signaling, but also negatively impacts IFNAR1 surface expression which is stabilised by TYK2. The STAT family of transcription factors are major mediators of the type I IFN response. This thesis demonstrates STAT activation by the type I IFNs occurs in a cell-type specific manner. STAT1 is up-regulated by type I IFN in a broad range of immune cell types including thymic and peripheral T-cells, B-cells and macrphages whereas activation of STAT3 and STAT5 is more confined to the thymic T-cells. Type I IFN stimulation of thymic cells results in rapid phosphorylation of STAT1, STAT3 and STAT5 and the resultant transcriptional response results in the up-regulation of an array of genes involved in innate defence. The promoter regions of these genes are enriched in ISGF3, STAT1, STAT3 and STAT5 binding elements. Results of this thesis demonstrate that the downstream consequence of SOCS1 action is to suppress IFN induced STAT activation and subsequent gene induction. We found SOCS1 selectively regulates STAT phosphorylation in response to IFNα. The activation profile of STAT1 and STAT3 is altered by SOCS1, whereas STAT5 is independent of this regulation. Using microarray expression profiling, we identified subsets of IFN stimulated genes regulated by SOCS1. Promoter analysis of these gene sets identifies transcription factor enrichment of numerous ISGF3, STAT1 and STAT3 binding sites but not STAT5. These results support a model whereby SOCS1 negative regulation of type I IFN signaling selectively modulates the activation profile of STAT1 and STAT3 and consequent gene induction. These studies have mapped specific pathways of IFN regulation from the receptor component to transcription factor activation and interferon regulated gene induction. I demonstrate that SOCS1 selectively interacts with the IFNAR1 associated kinase, TYK2 and regulates the signaling of a subset of IFN activated STATs and IFN/STAT regulated genes. These findings therefore enhance our understanding of type I IFN signaling and its regulation by SOCS1 and provide the foundation for future therapies to select for specific type I IFN signaling pathways.