CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis.

Therapeutic Approaches

Abstract

CD47 is a surface receptor that induces either coactivation or apoptosis in lymphocytes, depending on the ligand(s) bound. Interestingly, the apoptotic pathway is independent of caspase activation and cytochrome c release and is accompanied by early mitochondrial dysfunction with suppression of mitochondrial membrane potential (Deltapsim). Using CD47 as bait in a yeast two-hybrid system, we identified the Bcl-2 homology 3 (BH3)-only protein 19 kDa interacting protein-3 (BNIP3), a pro-apoptotic member of the Bcl-2 family, as a novel partner. Interaction between CD47 and the BH3-only protein was confirmed by immunoprecipitation analysis, and CD47-induced apoptosis was inhibited by attenuating BNIP3 expression with antisense oligonucleotides. Finally, we showed that the C-terminal domain of thrombospondin-1 (TSP-1), but not signal-regulatory protein (SIRPalpha1), is the ligand for CD47 involved in inducing cell death. Immunofluorescence analysis of CD47 and BNIP3 revealed a partial colocalization of both molecules under basal conditions. After T cell stimulation via CD47, BNIP3 translocates to the mitochondria to induce apoptosis. These results show that the BH3-dependent apoptotic pathways, previously shown to be activated by intracellular pro-apoptotic events, can also be turned on by surface receptors. This new pathway results in a fast induction of cell death resembling necrosis, which is likely to play an important role in lymphocyte regulation at inflammatory sites and/or in the vicinity of thrombosis.

Authors

Lamy, Laurence; Ticchioni, Michel; Rouquette-Jazdanian, Alexandre K; Samson, Michel; Deckert, Marcel; Greenberg, Arnold H; Bernard, Alain;

Keywords

  • Antigens, CD/ physiology
  • Antigens, CD47
  • Apoptosis
  • Carrier Proteins/ physiology
  • Humans
  • Jurkat Cells
  • Membrane Proteins/ metabolism
  • Membrane Proteins/ physiology
  • Mitochondria/ chemistry
  • Mitochondria/ pathology
  • Protein Transport
  • Proto-Oncogene Proteins
  • Signal Transduction
  • Solubility
  • T-Lymphocytes/ cytology
  • T-Lymphocytes/ metabolism
  • T-Lymphocytes/ ultrastructure
  • Thrombospondin 1/ chemistry
  • Thrombospondin 1/ metabolism
  • Tumor Suppressor Proteins
  • Two-Hybrid System Techniques

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