Phosphorylation of Nur77 by the MEK-ERK-RSK Cascade Induces Mitochondrial Translocation and Apoptosis in T Cells

被引:73
作者
Wang, Aibo
Rud, Jonathan [2 ]
Olson, Chris M., Jr.
Anguita, Juan [2 ]
Osborne, Barbara A. [1 ,2 ]
机构
[1] Univ Massachusetts, Paige Lab 311, Dept Vet & Anim Sci, Amherst, MA 01003 USA
[2] Univ Massachusetts, Program Mol & Cellular Biol, Amherst, MA 01003 USA
关键词
ORPHAN STEROID-RECEPTOR; N-TERMINAL KINASE; NEGATIVE SELECTION; NUCLEAR RECEPTOR; NGFI-B; ACTIVATION; BCL-2; THYMOCYTES; FAMILY; REQUIREMENT;
D O I
10.4049/jimmunol.0900894
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Nur77, an orphan nuclear receptor, plays a key role in apoptosis in T cells. In cancer cell lines, Nur77 can induce apoptosis through the intrinsic apoptotic pathway, but the mechanism by which Nur77 kills T cells remains controversial. In this study, we provide biochemical, pharmacological, and genetic evidence demonstrating that Nur77 induces apoptosis through the activation of the intrinsic pathway in T cells. We also show that Nur77 is a physiological substrate of the MEK-ERK-RSK cascade. Specifically, we demonstrate that RSK phosphorylates Nur77 at serine 354 and this modulates Nur77 nuclear export and intracellular translocation during T cell death. Our data reveal that Nur77 phosphorylation and mitochondrial targeting, regulated by RSK, defines a role for the MEK1/2-ERK1/2 cascade in T cell apoptosis. The Journal of Immunology, 2009, 183: 3268-3277.
引用
收藏
页码:3268 / 3277
页数:10
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