Deltex regulates T-cell activation by targeted degradation of active MEKK1.
Deltex is known as a Notch signal mediator, but its physiological action mechanism is poorly understood. Here we identified a new regulatory role of Deltex in T-cell activation. Deltex expression was constitutive in resting T cells and was reduced upon T-cell receptor (TCR)-stimulated activation. The biological role of Deltex is supported by the enhanced T-cell activation when Deltex1 was down-regulated by small interfering RNA. Overexpression of Deltex1 suppressed T-cell activation but not the proximal TCR activation events. The impaired activation of mitogen-activated protein kinase by Deltex could be partly attributed to a selective down-regulation of MEKK1 protein in T cells. We further found that Deltex promoted degradation of the C-terminal catalytic fragment of MEKK1 [MEKK1(C)]. Deltex1 interacted directly with MEKK1(C) and stimulated the ubiquitination of MEKK1(C) as shown by in vivo and in vitro ubiquitination analysis. Therefore, MEKK1(C), the dominant form of MEKK1 in T cells, is a target of Deltex E3 ubiquitin ligase. Our results reveal a novel mechanism as to how Deltex selectively suppresses T-cell activation through degradation of a key signaling molecule, MEKK1.
Liu
Wen-Hsien
WH
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China. mblai@ccvax.sinica.edu.tw
Lai
Ming-Zong
MZ
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011489:Protein Denaturation / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D034741:RNA, Small Interfering; D025801:Ubiquitin; C104035:Dtx1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D048728:MAP Kinase Kinase Kinase 1