The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease

Youcun Qian; Caini Liu; Justin Hartupee; Cengiz Zubeyir Altuntas; Muhammet Fatih Gulen; Daniel Jane-Wit; Jianhua Xiao; Yi Lu; Natalia Giltiay; Jinbo Liu; Tomasz Kordula; Qi-Wei Zhang; Bruce Vallance; Shadi Swaidani; Mark Aronica; Vincent K Tuohy; Thomas Hamilton; Xiaoxia Li

doi:10.1038/ni1439

The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease

Nat Immunol. 2007 Mar;8(3):247-56. doi: 10.1038/ni1439. Epub 2007 Feb 4.

Authors

Youcun Qian¹, Caini Liu, Justin Hartupee, Cengiz Zubeyir Altuntas, Muhammet Fatih Gulen, Daniel Jane-Wit, Jianhua Xiao, Yi Lu, Natalia Giltiay, Jinbo Liu, Tomasz Kordula, Qi-Wei Zhang, Bruce Vallance, Shadi Swaidani, Mark Aronica, Vincent K Tuohy, Thomas Hamilton, Xiaoxia Li

Affiliation

¹ Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.

PMID: 17277779
DOI: 10.1038/ni1439

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / immunology*
Adaptor Proteins, Signal Transducing / metabolism
Adoptive Transfer
Animals
Autoimmune Diseases*
Autoimmunity
B-Cell Activation Factor Receptor / immunology
B-Cell Activation Factor Receptor / metabolism
CD40 Antigens / immunology
CD40 Antigens / metabolism
Colitis / immunology
Colitis / metabolism
Colitis / pathology
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / metabolism
Encephalomyelitis, Autoimmune, Experimental / pathology
Enzyme-Linked Immunosorbent Assay
Female
Fluorescent Antibody Technique
Gene Expression
Gene Expression Regulation / immunology
HeLa Cells
Humans
Inflammation / immunology*
Interleukin-17 / immunology*
Interleukin-17 / metabolism
Mice
Receptors, Interleukin-17 / immunology
Receptors, Interleukin-17 / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / immunology*
T-Lymphocytes / immunology
Transfection
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Substances

Adaptor Proteins, Signal Transducing
B-Cell Activation Factor Receptor
CD40 Antigens
IL17RA protein, human
Interleukin-17
Receptors, Interleukin-17
TRAF3IP2 protein, human
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding