The Siva protein is a novel intracellular ligand of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells.
In addition to its positive signaling function in the antigen presentation process, CD4 acts as the primary receptor for HIV-1. Contact between CD4 and the viral envelope leads to virus entry, but can also trigger apoptosis of uninfected CD4+ T-cells through a mechanism that is poorly understood. We show that Siva-1, a death domain-containing proapoptotic protein, associates with the cytoplasmic domain of CD4. This interaction is mediated by the cysteine-rich region found in the C-terminal part of the Siva-1 protein. Expression of Siva-1 specifically increases the susceptibility of both T-cell lines and unstimulated human primary CD4+ T-lymphocytes to CD4-mediated apoptosis triggered by the HIV-1 envelope, and results in activation of a caspase-dependent mitochondrial pathway. The same susceptibility is observed in T-cells expressing a truncated form of CD4 that is able to recruit Siva-1 but fails to associate with p56Lck, indicating that Siva-1 participates in a pathway independent of the p56Lck kinase activity. Altogether, these results suggest that Siva-1 might participate in the CD4-initiated signaling apoptotic pathway induced by the HIV-1 envelope in T-lymphoid cells.
Py
Bénédicte
B
Institut Cochin, CNRS (UMR 8104), Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France.
Bouchet
Jérôme
J
Jacquot
Guillaume
G
Sol-Foulon
Nathalie
N
Basmaciogullari
Stéphane
S
Schwartz
Olivier
O
Biard-Piechaczyk
Martine
M
Benichou
Serge
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D015497:HIV-1 / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015704:CD4 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D011993:Recombinant Fusion Proteins; C106549:SIVA1 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein