Dual-specificity phosphatase 14 (DUSP14/MKP6) negatively regulates TCR signaling by inhibiting TAB1 activation

J Immunol. 2014 Feb 15;192(4):1547-57. doi: 10.4049/jimmunol.1300989. Epub 2014 Jan 8.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Enzyme Activation / immunology
  • Humans
  • I-kappa B Kinase / metabolism
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / biosynthesis
  • Interleukin-4 / biosynthesis
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Jurkat Cells
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • MAP Kinase Kinase Kinases / metabolism*
  • MAP Kinase Signaling System / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell / metabolism*
  • Th1 Cells / immunology
  • Th17 Cells / immunology
  • Transforming Growth Factor beta / metabolism
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adaptor Proteins, Signal Transducing
  • Interleukin-2
  • Multiprotein Complexes
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • Tab1 protein, mouse
  • Transforming Growth Factor beta
  • Interleukin-4
  • Interferon-gamma
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Dual-Specificity Phosphatases
  • Dusp14 protein, mouse