title: Active caspase-8 translocates into the nucleus of apoptotic cells to inactivate poly(ADP-ribose) polymerase-2.
abstract: Caspase-8 is the prototypic initiator of the death domain receptor pathway of apoptosis. Here, we report that caspase-8 not only triggers and amplifies the apoptotic process at cytoplasmic sites but can also act as an executioner at nuclear levels. In a murine model of acute ischemia, caspase-8 is relocated into the nucleus of apoptotic neurons, where it cleaves PARP-2, a member of the poly(ADP-ribose) polymerase family involved in DNA repair. As indicated by site-directed mutagenesis, PARP-2 cleavage occurs preferentially at the LQMD sequence mapped between the DNA binding and the catalytic domains of the protein. This is close to the cleavage sequence found in Bid, the cytoplasmic target of caspase-8. Activity assays confirm that cleavage of PARP-2 results in inactivation of its poly(ADP-ribosylation) property, proportional to the efficiency of the cleavage. Our findings add to the complexity of proteolytic caspase networks by demonstrating that caspase-8 is in turn an initiator, amplifier, and effector caspase.
authors.affiliation: INSERM U 421, Université Paris Val-de-Marne, 8 rue du General Sarrail, F-94010 Créteil cedex, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benchoua
authors.forename: Cécile
authors.initials: C
authors.lastname: Couriaud
authors.forename: Christelle
authors.initials: C
authors.lastname: Guégan
authors.forename: Laurence
authors.initials: L
authors.lastname: Tartier
authors.forename: Philippe
authors.initials: P
authors.lastname: Couvert
authors.forename: Gaelle
authors.initials: G
authors.lastname: Friocourt
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Josiane
authors.initials: J
authors.lastname: Ménissier-de Murcia
authors.forename: Brigitte
authors.initials: B
authors.lastname: Onténiente
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology*; D002467:Cell Nucleus / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
chemical_list: D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases