Induction of β-R1/I-TAC by interferon-β requires catalytically active TYK2

Abstract

The β-R1/I-TAC (interferon-inducible T-cell α-chemoattractant) gene encodes an α-chemokine that is a potent chemoattractant for activated T- cells. We previously reported that β-R1 was selectively induced by interferon (IFN)-β compared with IFN-α and that the canonical type I IFN transcription factor interferon-stimulated gene factor 3 (ISGF3) was necessary but not sufficient for β-R1 induction by IFN-β. These findings suggested that β-R1 induction by IFN-β required an accessory component. To begin characterizing this signaling pathway, we examined the function of TYK2 protein in the IFN-β-mediated induction of β-R1. This study was motivated by the observation that β-R1 could not be induced in TYK2-deficient U1 cells by IFN-β (Rani, M. R. S., Foster, G. R., Leung, S., Leaman, D., Stark, G. R., and Ransohoff, R. M. (1996) J. Biol. Chem. 271, 22878-22884), an unexpected result because IFN-β evokes substantial expression of IFN- stimulated genes (ISGs) in U1 cells through a TYK2-independent pathway. We now report β-R1 expression patterns in U1 cells complemented with wild-type or mutant TYK2 proteins. Complementation with wild-type TYK2 rescued IFN-β- inducible expression of β-R1. Cells expressing kinase-deficient deletion or point mutants of TYK2 were refractory to induction of β-R1 by IFN-β despite robust expression of other ISGs. Transient transfection analysis of a β-R1 promoter-reporter confirmed that transcriptional activation of β-R1 by IFN- β required competent TYK2 kinase. These studies indicate that the catalytic function of TYK2 is required for IFN-β-mediated induction of β-R1. Catalytic TYK2 is the first identified component in an accessory signaling pathway that supplements ISGF3/interferon-stimulated response element signaling for gene induction by type I IFNs.