Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos)

Yingfei Wang, No Soo Kim, Jean Francois Haince, Ho Chul Kang, Karen K. David, Shaida A. Andrabi, Guy G. Poirier, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

211 Scopus citations

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.

Original languageEnglish (US)
Article numberra20
JournalScience Signaling
Volume4
Issue number167
DOIs
StatePublished - Apr 5 2011

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Wang, Y., Kim, N. S., Haince, J. F., Kang, H. C., David, K. K., Andrabi, S. A., Poirier, G. G., Dawson, V. L., & Dawson, T. M. (2011). Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Science Signaling, 4(167), [ra20]. https://doi.org/10.1126/scisignal.2000902