CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis.
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.
Lamy
Laurence
L
Unité INSERM 576 et Laboratoire d'Immunologie, 06202 Nice cedex 3, France.
Ticchioni
Michel
M
Rouquette-Jazdanian
Alexandre K
AK
Samson
Michel
M
Deckert
Marcel
M
Greenberg
Arnold H
AH
Bernard
Alain
A
D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008928:Mitochondria / Q000737:chemistry / Q000473:pathology; D021381:Protein Transport; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D019700:Thrombospondin 1 / Q000737:chemistry / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
D015703:Antigens, CD; C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019700:Thrombospondin 1; D025521:Tumor Suppressor Proteins