During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain.
Apoptosis accompanying negative selection is a central but poorly understood event in T cell development. The Nur77 nuclear steroid receptor and Bim, a proapoptotic BH3-only member of the Bcl-2 family, are two molecules implicated in this process. However, how they relate to each other and how Nur77 induces apoptosis remain unclear. In thymocytes, Nur77 has been shown to induce cell death through a transcriptional-dependent pathway, but in cancer cell lines, Nur77 was reported to induce apoptosis through conversion of Bcl-2 into a killer protein at the mitochondria. Whether this Nur77 transcriptional-independent pathway actually occurs in vivo remains controversial. Using an optimized fractionation protocol for thymocytes, here we report that stimulation of CD4(+)CD8(+) thymocytes results in translocation of Nur77 and its family member Nor-1 to the mitochondria, leading to their association with Bcl-2 and exposure of the Bcl-2 proapoptotic BH3 domain. In two T cell receptor transgenic models of negative selection, F5 and HY, a conformational change of the Bcl-2 molecule in the negatively selected T cell population was similarly observed. Thus, the Nur77 family and Bim pathways converge at mitochondria to mediate negative selection.
Thompson
Jennifer
J
Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Winoto
Astar
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010446:Peptide Fragments / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; C539821:NR4A1 protein, human; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate; C038753:leptomycin B