title: Dual-specificity phosphatase 14 (DUSP14/MKP6) negatively regulates TCR signaling by inhibiting TAB1 activation.
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.
authors.affiliation: Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan;
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Yang
authors.forename: Ju-Pi
authors.initials: JP
authors.lastname: Li
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Chiu
authors.forename: Joung-Liang
authors.initials: JL
authors.lastname: Lan
authors.forename: Der-Yuan
authors.initials: DY
authors.lastname: Chen
authors.forename: Huai-Chia
authors.initials: HC
authors.lastname: Chuang
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: Tse-Hua
authors.initials: TH
authors.lastname: Tan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054637:Dual-Specificity Phosphatases; D051550:I-kappa B Kinase; D007371:Interferon-gamma; D007376:Interleukin-2; D015847:Interleukin-4; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse; C498844:Dusp14 protein, mouse