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 interferon (IFN)-beta compared with IFN-alpha and that the canonical type I IFN transcription factor interferon- stimulated gene factor 3 ( ISGF3) was necessary but not sufficient for beta-R1 induction by IFN-beta. These findings suggested 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 was motivated by the observation that beta-R1 could not be induced in TYK2-deficient U1 cells by IFN-beta (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-beta evokes substantial expression of IFN- stimulated genes (ISGs) in U1 cells through a TYK2-independent pathway. We now report beta-R1 expression patterns in U1 cells complemented with wild-type or mutant TYK2 proteins. Complementation with wild-type TYK2 rescued IFN-beta-inducible expression of beta-R1. Cells expressing kinase-deficient deletion or point mutants of TYK2 were refractory to induction of beta-R1 by IFN-beta despite robust expression of other ISGs. Transient transfection analysis of a beta-R1 promoter-reporter confirmed that transcriptional activation of beta-R1 by IFN-beta required competent TYK2 kinase. These studies indicate that the catalytic function of TYK2 is required for IFN-beta-mediated induction of beta-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.[1]References
- Induction of beta-R1/I-TAC by interferon-beta requires catalytically active TYK2. Rani, M.R., Gauzzi, C., Pellegrini, S., Fish, E.N., Wei, T., Ransohoff, R.M. J. Biol. Chem. (1999) [Pubmed]
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