國家衛生研究院 NHRI:Item 3990099045/12449
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    题名: Induction of TRAF2-mediated DUSP14/MKP6 ubiquitination by PRMT5-mediated arginine methylation
    作者: Tan, T
    贡献者: Immunology Research Center
    摘要: Dual specificity phosphatase 14 (DUSP14, also known as MKP6) inhibits T cell receptor (TCR) signaling and T cell mediated immune responses by inactivation of TAB1 TAK1 complex and ERK. DUSP14 indirectly interacts with TAK1 through TAB1; thus, DUSP14 inhibits T cell activation by dephosphorylating TAB1, leading to inactivation of TAK1, IKK, and JNK during T cell receptor (TCR) signaling. DUSP14 is Lys63 linked ubiquitination by the E3 ligase TRAF2, and the ubiquitination stimulates its phosphatase activity during T cell signaling. We identified a novel DUSP14 interacting protein, PRMT5, and studied whether DUSP14 is regulated by PRMT5 during T cell signaling. We found that DUSP14 directly interacted with protein arginine methyltransferase 5 (PRMT5) using proximity ligation (PLA) assay; similarly, DUSP14 directly interacted with TAB1 but not TAK1. Arginine methylation of DUSP14 by PRMT5 stimulated the interaction between DUSP14 and TRAF2, as well as subsequent DUSP14 ubiquitination. We have mapped three arginine residues on DUSP14 that are methylated by PRMT5 using mass spectrometry. The DUSP14 triple methylation mutant was impaired in PRMT5 mediated arginine methylation, TRAF2 mediated lysine ubiquitination, and DUSP14 phosphatase activity. Consistently, DUSP14 methylation, TRAF2 binding, and DUSP14 ubiquitination were attenuated by PRMT5 shRNA knockdown. Furthermore, DUSP14 was inducibly interacted with PRMT5 and was methylated during TCR signaling in T cells. Together, these findings reveal a novel regulatory mechanism of DUSP14 by which PRMT5 mediated arginine methylation sequentially stimulates TRAF2 mediated DUSP14 ubiquitination and phosphatase activity, leading to inhibition of TCR signaling, a.k.a. inactivation of TAB1, IKK, JNK, and ERK.
    日期: 2018-12
    關聯: Molecular Biology of the Cell. 2018 Dec;29(26):Abstract number P1574.
    Link to: http://dx.doi.org/10.1091/mbc.E18-10-0647
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1059-1524&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000505772701132
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