Active caspase-8 translocates into the nucleus of apoptotic cells to inactivate poly(ADP-ribose) polymerase-2.
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.
Benchoua
Alexandra
A
INSERM U 421, Université Paris Val-de-Marne, 8 rue du General Sarrail, F-94010 Créteil cedex, France.
Couriaud
Cécile
C
Guégan
Christelle
C
Tartier
Laurence
L
Couvert
Philippe
P
Friocourt
Gaelle
G
Chelly
Jamel
J
Ménissier-de Murcia
Josiane
J
Onténiente
Brigitte
B
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*
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