Deltex Regulates T-Cell Activation by Targeted Degradation of Active MEKK1

Abstract

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.

ACKNOWLEDGMENTS

We thank Hideyuki Okano, Melanie Cobb, Dennis Templeton, Gina Costa, Garry Nolan, Ellen Rothenberg, Tse-Hua Tan, and Nan-Shih Liao for providing key materials used in this study and Ken Deen for editorial correction of the manuscript.

This work was supported by grant 92-2320-B001-006 from the National Science Council, Taiwan, grant NHRI-EX93-9217BI from the National Health Research Institute, Taiwan, and a grant from Academia Sinica.