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Cell Signal. 2016 Jan;28(1):145-51. doi: 10.1016/j.cellsig.2015.10.017. Epub 2015 Oct 28.

TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity.

Author information

1
Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan.
2
Department of Medical Education & Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
3
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.

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.

KEYWORDS:

DUSP14/MKP6; T-cell receptor signaling; TRAF2; Ubiquitination

PMID:
26521044
DOI:
10.1016/j.cellsig.2015.10.017
[Indexed for MEDLINE]

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