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

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 Lys63linked 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. (C) 2015 Elsevier Inc All rights reserved.