title: The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.
abstract: T helper cells that produce interleukin 17 (IL-17) are associated with inflammation and the control of certain bacteria. We report here the essential involvement of the adaptor protein Act1 in IL-17 receptor (IL-17R) signaling and IL-17-dependent immune responses. After stimulation with IL-17, recruitment of Act1 to IL-17R required the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which mediate 'downstream' activation of transcription factor NF-kappaB. IL-17-induced expression of inflammation-related genes was abolished in Act1-deficient primary astroglial and gut epithelial cells. This reduction was associated with much less inflammatory disease in vivo in both autoimmune encephalomyelitis and dextran sodium sulfate-induced colitis. Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease.
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Youcun
authors.initials: Y
authors.lastname: Qian
authors.forename: Caini
authors.initials: C
authors.lastname: Liu
authors.forename: Justin
authors.initials: J
authors.lastname: Hartupee
authors.forename: Cengiz Zubeyir
authors.initials: CZ
authors.lastname: Altuntas
authors.forename: Muhammet Fatih
authors.initials: MF
authors.lastname: Gulen
authors.forename: Daniel
authors.initials: D
authors.lastname: Jane-Wit
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xiao
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Natalia
authors.initials: N
authors.lastname: Giltiay
authors.forename: Jinbo
authors.initials: J
authors.lastname: Liu
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kordula
authors.forename: Qi-Wei
authors.initials: QW
authors.lastname: Zhang
authors.forename: Bruce
authors.initials: B
authors.lastname: Vallance
authors.forename: Shadi
authors.initials: S
authors.lastname: Swaidani
authors.forename: Mark
authors.initials: M
authors.lastname: Aronica
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Tuohy
authors.forename: Thomas
authors.initials: T
authors.lastname: Hamilton
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases; D015551:Autoimmunity; D053265:B-Cell Activation Factor Receptor / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D053722:Receptors, Interleukin-17 / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053265:B-Cell Activation Factor Receptor; D019013:CD40 Antigens; C109985:IL17RA protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins