title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Py
authors.forename: Christian
authors.initials: C
authors.lastname: Slomianny
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.forename: Patrice X
authors.initials: PX
authors.lastname: Petit
authors.forename: Serge
authors.initials: S
authors.lastname: Benichou
mesh_terms: 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
chemical_list: 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