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

The beta-R1/I-TAC (interferon-inducible T-cell alpha-chemoattractant) gene encodes an alpha-chemokine that is a potent chemoattractant for activated T -cells. We previously reported that beta-R1 was selectively induced by inte rferon (IFN)-beta compared with IFN-alpha and that the canonical type I IFN transcription factor interferon-stimulated gene factor 3 (ISGF3) was neces sary but not sufficient for beta-R1 induction by IFN-beta. These findings s uggested that beta-R1 induction by IFN-beta required an accessory component . To begin characterizing this signaling pathway, we examined the function of TYK2 protein in the IFN-beta-mediated induction of beta-R1. This study w as motivated by the observation that beta-R1 could not be induced in TYK2-d eficient U1 cells by IFN-beta (Rani, M, R, S., Foster, G;. R,, Leung, S,, L eaman, D,, Stark, G. R,, and Ransohoff, R. IM, (1996) J. Biol. Chem. 271, 2 2878-22884), an unexpected result because IFN-beta evokes substantial expre ssion of IFN-stimulated genes (ISGs) in U1 cells through a TYK2-independent pathway. We now report beta-R1 expression patterns in U1 cells complemente d with wild-type or mutant TYK2 proteins. Complementation with wild-type TY K2 rescued IFN-beta-inducible expression of beta-R1. Cells expressing kinas e-deficient deletion or point mutants of TYK2 were refractory to induction of beta-R1 by IFN-beta despite robust expression of other ISGs. Transient t ransfection analysis of a beta-R1 promoter-reporter confirmed that transcri ptional activation of beta-R1 by IFN-beta required competent TYK2 kinase, T hese studies indicate that the catalytic function of TYK2 is required for I FN-beta-mediated induction of beta-R1, Catalytic TYK2 is the first identifi ed component in an accessory signaling pathway that supplements ISGF3/inter feron-stimulated response element signaling for gene induction by type I IF Ns.