The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.
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.
Qian
Youcun
Y
Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Liu
Caini
C
Hartupee
Justin
J
Altuntas
Cengiz Zubeyir
CZ
Gulen
Muhammet Fatih
MF
Jane-Wit
Daniel
D
Xiao
Jianhua
J
Lu
Yi
Y
Giltiay
Natalia
N
Liu
Jinbo
J
Kordula
Tomasz
T
Zhang
Qi-Wei
QW
Vallance
Bruce
B
Swaidani
Shadi
S
Aronica
Mark
M
Tuohy
Vincent K
VK
Hamilton
Thomas
T
Li
Xiaoxia
X
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
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