Abstract
T cell activation is dependent upon phosphorylation of MAPKs, which play a critical role in the regulation of immune responses. Dual-specificity phosphatase 14 (DUSP14; also known as MKP6) is classified as a MAPK phosphatase. The in vivo functions of DUSP14 remain unclear. Thus, we generated DUSP14-deficient mice and characterized the roles of DUSP14 in T cell activation and immune responses. DUSP14 deficiency in T cells resulted in enhanced T cell proliferation and increased cytokine production upon T cell activation. DUSP14 directly interacted with TGF-β-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser(438), leading to TAB1-TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1-TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Differentiation / immunology
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Cell Proliferation
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Dual-Specificity Phosphatases / genetics
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Dual-Specificity Phosphatases / metabolism*
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Enzyme Activation / immunology
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Humans
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I-kappa B Kinase / metabolism
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Interferon-gamma / biosynthesis
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Interleukin-2 / biosynthesis
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Interleukin-4 / biosynthesis
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JNK Mitogen-Activated Protein Kinases / metabolism
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Jurkat Cells
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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MAP Kinase Kinase Kinases / metabolism*
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MAP Kinase Signaling System / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes / metabolism
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Phosphorylation
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Protein Binding
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RNA Interference
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RNA, Small Interfering
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Receptors, Antigen, T-Cell / metabolism*
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Th1 Cells / immunology
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Th17 Cells / immunology
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Transforming Growth Factor beta / metabolism
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Interleukin-2
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Multiprotein Complexes
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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Tab1 protein, mouse
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Transforming Growth Factor beta
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Interleukin-4
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Interferon-gamma
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I-kappa B Kinase
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Dual-Specificity Phosphatases
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Dusp14 protein, mouse