Abstract
Reversible ubiquitin modification of cell signaling molecules has emerged as a critical mechanism by which cells respond to extracellular stimuli. Although ubiquitination of TGF-β-activated kinase 1 (TAK1) is critical for NF-κB activation in T cells, the regulation of its deubiquitination is unclear. We show that USP18, which was previously reported to be important in regulating type I interferon signaling in innate immunity, regulates T cell activation and T helper 17 (Th17) cell differentiation by deubiquitinating the TAK1-TAB1 complex. USP18-deficient T cells are defective in Th17 differentiation and Usp18(-/-) mice are resistant to experimental autoimmune encephalomyelitis (EAE). In response to T cell receptor engagement, USP18-deficient T cells exhibit hyperactivation of NF-κB and NFAT and produce increased levels of IL-2 compared with the wild-type controls. Importantly, USP18 is associated with and deubiquitinates the TAK1-TAB1 complex, thereby restricting expression of IL-2. Our findings thus demonstrate a previously uncharacterized negative regulation of TAK1 activity during Th17 differentiation, suggesting that USP18 may be targeted to treat autoimmune diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Autoimmune Diseases / immunology
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Autoimmune Diseases / metabolism
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Catalysis
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Endopeptidases / genetics
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Endopeptidases / metabolism*
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Gene Expression
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Gene Knockout Techniques
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / metabolism
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MAP Kinase Kinase Kinases / metabolism*
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Mice
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Mice, Knockout
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NF-kappa B / metabolism*
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NFATC Transcription Factors / metabolism*
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Protein Binding
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Th17 Cells / cytology*
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Th17 Cells / immunology
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Th17 Cells / metabolism*
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Ubiquitin Thiolesterase
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Ubiquitination
Substances
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Adaptor Proteins, Signal Transducing
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Interleukin-2
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NF-kappa B
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NFATC Transcription Factors
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Receptors, Antigen, T-Cell
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Tab1 protein, mouse
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Endopeptidases
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Usp18 protein, mouse
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Ubiquitin Thiolesterase