title: TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity.
abstract: Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) is a MAP kinase phosphatase that dephosphorylates JNK, ERK, and p38 in vitro. We recently reported that DUSP14 negatively regulates T-cell activation and immune responses by interfering activation of TAB1-TAK1 complex. However, the molecular mechanism that regulates the phosphatase activity of DUSP14 remains unclear. Here, we report the post-translational modification of DUSP14 by ubiquitination. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue. Furthermore, DUSP14 inducibly interacted with the E3 ligase TRAF2 during T-cell receptor (TCR) signaling; TRAF2 shRNA knockdown reduced the DUSP14 ubiquitination. We also show that ubiquitination of DUSP14 was required for its phosphatase activity during TCR signaling. Together, these findings reveal a novel mechanism by which TRAF2 mediates Lys63-linked ubiquitination of DUSP14, leading to DUSP14 activation in T cells.
authors.affiliation: Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Medical Education & Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Chiu
authors.affiliation: Research and Development Center for Immunology, China Medical University, Taichung 40402, Taiwan; Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: ttan@nhri.org.tw.
authors.forename: Tse-Hua
authors.initials: TH
authors.lastname: Tan
mesh_terms: D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008239:Lysine / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D025801:Ubiquitin; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; C498843:DUSP14 protein, human; D054637:Dual-Specificity Phosphatases; D008239:Lysine
keywords: DUSP14/MKP6; T-cell receptor signaling; TRAF2; Ubiquitination