title: Induction of beta-R1/I-TAC by interferon-beta requires catalytically active TYK2.
abstract: 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.
authors.affiliation: Department of Neurosciences, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Rani
authors.forename: C
authors.initials: C
authors.lastname: Gauzzi
authors.forename: S
authors.initials: S
authors.lastname: Pellegrini
authors.forename: E N
authors.initials: EN
authors.lastname: Fish
authors.forename: T
authors.initials: T
authors.lastname: Wei
authors.forename: R M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D002384:Catalysis; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D004247:DNA; D005786:Gene Expression Regulation; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion; D053634:TYK2 Kinase; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: C515202:CXCL11 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D011506:Proteins; D012333:RNA, Messenger; D016899:Interferon-beta; D004247:DNA; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human