title: Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos).
abstract: The mitochondrial protein apoptosis-inducing factor (AIF) plays a pivotal role in poly(ADP-ribose) polymerase-1 (PARP-1)-mediated cell death (parthanatos), during which it is released from the mitochondria and translocates to the nucleus. We show that AIF is a high-affinity poly(ADP-ribose) (PAR)-binding protein and that PAR binding to AIF is required for parthanatos both in vitro and in vivo. AIF bound PAR at a site distinct from AIF's DNA binding site, and this interaction triggered AIF release from the cytosolic side of the mitochondrial outer membrane. Mutation of the PAR binding site in AIF did not affect its NADH (reduced form of nicotinamide adenine dinucleotide) oxidase activity, its ability to bind FAD (flavin adenine dinucleotide) or DNA, or its ability to induce nuclear condensation. However, this AIF mutant was not released from mitochondria and did not translocate to the nucleus or mediate cell death after PARP-1 activation. These results suggest a mechanism for PARP-1 to initiate AIF-mediated cell death and indicate that AIF's bioenergetic cell survival-promoting functions are separate from its effects as a mitochondrially derived death effector. Interference with the PAR-AIF interaction or PAR signaling may provide notable opportunities for preventing cell death after activation of PARP-1.
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Wang
authors.forename: No Soo
authors.initials: NS
authors.lastname: Kim
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Haince
authors.forename: Ho Chul
authors.initials: HC
authors.lastname: Kang
authors.forename: Karen K
authors.initials: KK
authors.lastname: David
authors.forename: Shaida A
authors.initials: SA
authors.lastname: Andrabi
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
mesh_terms: D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D001483:Base Sequence; D016923:Cell Death / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005822:Genetic Vectors / Q000235:genetics; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016086:Lentivirus; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: D051033:Apoptosis Inducing Factor; D011064:Poly Adenosine Diphosphate Ribose; D001120:Arginine; D011065:Poly(ADP-ribose) Polymerases; D008239:Lysine