Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Sci. Signal., 5 April 2011
Vol. 4, Issue 167, p. ra20
[DOI: 10.1126/scisignal.2000902]

RESEARCH ARTICLES

Poly(ADP-Ribose) (PAR) Binding to Apoptosis-Inducing Factor Is Critical for PAR Polymerase-1–Dependent Cell Death (Parthanatos)

Yingfei Wang1,2, No Soo Kim1,2*, Jean-Francois Haince3, Ho Chul Kang1,2, Karen K. David1,2,4{dagger}, Shaida A. Andrabi1,2, Guy G. Poirier3, Valina L. Dawson1,2,4,5,6{ddagger}, and Ted M. Dawson1,2,4,5{ddagger}

1 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, BRB 731, Baltimore, MD 21205, USA.
2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Health and Environment Unit, Laval University Medical Research Center, CHUQ, Ste-Foy, Quebec, Canada G1V 4G2.
4 Graduate Program in Cellular and Molecular Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
5 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

* Present address: Brain Disease Research Center, Korea Institute of Oriental Medicine, 483 Expo-ro, Yuseong-gu, Daejeon 305-81, South Korea.

{dagger} Present address: Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 North Wolfe Street, PCTB 714, Baltimore, MD 21205, USA.

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.

{ddagger} To whom correspondence should be addressed. E-mail: tdawson{at}jhmi.edu (T.M.D.); vdawson{at}jhmi.edu (V.L.D.)

Citation: Y. Wang, N. S. Kim, J.-F. Haince, H. C. Kang, K. K. David, S. A. Andrabi, G. G. Poirier, V. L. Dawson, T. M. Dawson, Poly(ADP-Ribose) (PAR) Binding to Apoptosis-Inducing Factor Is Critical for PAR Polymerase-1–Dependent Cell Death (Parthanatos). Sci. Signal. 4, ra20 (2011).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survival.
P. Puthanveetil, A. Wan, and B. Rodrigues (2013)
Cardiovasc Res 97, 393-403
   Abstract »    Full Text »    PDF »
Mitochondrial Control of Cellular Life, Stress, and Death.
L. Galluzzi, O. Kepp, C. Trojel-Hansen, and G. Kroemer (2012)
Circ. Res. 111, 1198-1207
   Abstract »    Full Text »    PDF »
Quantitative proteomics and dynamic imaging reveal that G3BP-mediated stress granule assembly is poly(ADP-ribose)-dependent following exposure to MNNG-induced DNA alkylation.
M. Isabelle, J.-P. Gagne, I.-E. Gallouzi, and G. G. Poirier (2012)
J. Cell Sci. 125, 4555-4566
   Abstract »    Full Text »    PDF »
Inverse Susceptibility to Oxidative Death of Lymphocytes Obtained From Alzheimer's Patients and Skin Cancer Survivors: Increased Apoptosis in Alzheimer's and Reduced Necrosis in Cancer.
M. I. Behrens, M. Silva, F. Salech, D. P. Ponce, D. Merino, M. Sinning, C. Xiong, C. M. Roe, and A. F. G. Quest (2012)
J Gerontol A Biol Sci Med Sci 67, 1036-1040
   Abstract »    Full Text »    PDF »
Quantitative proteomics profiling of the poly(ADP-ribose)-related response to genotoxic stress.
J.-P. Gagne, E. Pic, M. Isabelle, J. Krietsch, C. Ethier, E. Paquet, I. Kelly, M. Boutin, K.-M. Moon, L. J. Foster, et al. (2012)
Nucleic Acids Res. 40, 7788-7805
   Abstract »    Full Text »    PDF »
Herpes Simplex Virus 1 Infection Activates Poly(ADP-Ribose) Polymerase and Triggers the Degradation of Poly(ADP-Ribose) Glycohydrolase.
S. L. Grady, J. Hwang, L. Vastag, J. D. Rabinowitz, and T. Shenk (2012)
J. Virol. 86, 8259-8268
   Abstract »    Full Text »    PDF »
A Dual Role for Poly(ADP-Ribose) Polymerase-1 * During Caspase-Dependent Apoptosis.
F. Zhang, S. S. Lau, and T. J. Monks (2012)
Toxicol. Sci. 128, 103-114
   Abstract »    Full Text »    PDF »
Mitochondrial P5, a member of protein disulphide isomerase family, suppresses oxidative stress-induced cell death.
Y. Shitara, Y. Tonohora, T. Goto, Y. Yamada, T. Miki, H. Makino, M. Miwa, and T. Komiya (2012)
J. Biochem. 152, 73-85
   Abstract »    Full Text »    PDF »
Serine/Threonine Phosphatase (SP-STP), Secreted from Streptococcus pyogenes, Is a Pro-apoptotic Protein.
S. Agarwal, S. Agarwal, H. Jin, P. Pancholi, and V. Pancholi (2012)
J. Biol. Chem. 287, 9147-9167
   Abstract »    Full Text »    PDF »
On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1.
X. Luo and W. L. Kraus (2012)
Genes & Dev. 26, 417-432
   Abstract »    Full Text »    PDF »
Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage.
H. C. Kang, Y.-I. Lee, J.-H. Shin, S. A. Andrabi, Z. Chi, J.-P. Gagne, Y. Lee, H. S. Ko, B. D. Lee, G. G. Poirier, et al. (2011)
PNAS 108, 14103-14108
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882