Wang Aibo, Rud Jonathan, Olson Chris M, Anguita Juan, Osborne Barbara A
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
J Immunol. 2009 Sep 1;183(5):3268-77. doi: 10.4049/jimmunol.0900894. Epub 2009 Aug 12.
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.
孤儿核受体Nur77在T细胞凋亡中起关键作用。在癌细胞系中，Nur77可通过内源性凋亡途径诱导凋亡，但Nur77杀死T细胞的机制仍存在争议。在本研究中，我们提供了生化、药理学和遗传学证据，证明Nur77通过激活T细胞内源性途径诱导凋亡。我们还表明，Nur77是MEK-ERK-RSK级联反应的生理底物。具体而言，我们证明RSK使Nur77的丝氨酸354磷酸化，这在T细胞死亡过程中调节Nur77的核输出和细胞内转运。我们的数据表明，由RSK调节的Nur77磷酸化和线粒体靶向作用，确定了MEK1/2-ERK1/2级联反应在T细胞凋亡中的作用。
