Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway.
Siva-1 is a death domain-containing proapoptotic protein identified as an intracellular ligand of CD27 and of the glucocorticoid-induced TNFR family-related gene, which are two members of the TNFR family expressed on lymphoid cells. Although Siva-1 expression is up-regulated in multiple pathological processes, little is known about the signaling pathway underlying the Siva-induced apoptosis. In this study, we investigated the mechanism of the proapoptotic activity of Siva-1 and an alternative splice form lacking the death domain of Siva-1, Siva-2, in T lymphocytes in which Siva proteins, CD27, and glucocorticoid-induced TNFR family-related gene are primarily expressed. Overexpression of Siva proteins triggers a typical apoptotic process manifested by cell shrinkage and surface exposure of phosphatidylserine, and confirmed by ultrastructural features. Siva-induced apoptosis is related to the CD27-mediated apoptotic pathway and results in activation of both initiator and effector caspases. This pathway involves a mitochondrial step evidenced by activation of Bid and cytochrome c release, and is modulated by overexpression of Bcl-2 or Bcl-x(L). The determinants for Siva-induced apoptosis are not contained within the death domain found in the central part of Siva-1, but rather in both the N-terminal and C-terminal regions shared by both Siva proteins. The N-terminal region also participates in the translocation of both Siva proteins into the nuclear compartment. These results indicate that Siva-1 and Siva-2 mediate apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway that likely involves both cytoplasmic and nuclear events.
Py
Bénédicte
B
Département de Maladies Infectieuses, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique UMR8104, Université Paris 5, Paris, France.
Slomianny
Christian
C
Auberger
Patrick
P
Petit
Patrice X
PX
Benichou
Serge
S
D017398:Alternative Splicing / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000502:physiology; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008928:Mitochondria / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010539:Permeability; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018984:Epitopes, T-Lymphocyte; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; C106549:SIVA1 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D020169:Caspases