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.
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