Type I interferons include more than l0 subtypes of IFN-alpha, as well as IFN-beta, IFN-tau and IFN-omega. These related cytokines all signal through the IFN alpha/beta receptor, a complex composed of two transmembrane components (IFNAR-l/2) and two nonreceptor protein tyrosine kinases, TYK2 and JAK1. It has recently become clear that diverse signals can be generated by engagement of this receptor complex with its various ligands. Two distinctive outcomes of treatment with IFN-beta have been described: inducible transcription of a gene termed beta-R1, and assembly of a stable complex of IFN-beta with the two receptor chains. We propose that the induction of beta-Rl requires both common and unique signaling through the IFNAR-l/2 complex. This hypothesis is based on our preliminary results, which demonstrate that beta-RI transcription is dependent on all components needed to form the transcription factor ISGF3, but is atypically sensitive to phosphoinositol-3 kinase (PI3K) inhibitors and exhibits an unusual requirement for catalytically active TYK2. This research proposal addresses the hypothesis that 13-RI transcription depends on conformation-dependent signaling through the IFNAR-1/2 complex in response to IFN-beta as compared with IFN-alpha. This signaling pathway acts through catalytic TYK2 and PI3K, as well as ISGF3.
The specific aims are to: l) characterize IFN-beta signaling to the beta3-Rl promoter; 2) generate cells selectively unresponsive to IFN-beta and 3) determine gene expression selectively regulated by IFN-beta. Performance of these aims will provide insight into IFN-beta-specific signaling and help clarify the functional roles of accessory components, such as PI3K, in type I IFN response pathway.
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