Phosphorylation of Nur77 by the MEK-ERK-RSK cascade induces mitochondrial translocation and apoptosis in T cells.
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.
Wang
Aibo
A
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
Rud
Jonathan
J
Olson
Chris M
CM
Anguita
Juan
J
Osborne
Barbara A
BA
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010766:Phosphorylation; D021381:Protein Transport / Q000276:immunology; D011987:Receptors, Steroid / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases