Nuclear-translocated glyceraldehyde-3-phosphate dehydrogenase promotes Poly(ADP-ribose) polymerase-1 activation during oxidative/nitrosative stress in stroke

Hidemitsu Nakajima, Takeya Kubo, Hideshi Ihara, Takatoshi Hikida, Teruko Danjo, Masatoshi Nakatsuji, Neelam Shahani, Masanori Itakura, Yoko Ono, Yasu Taka Azuma, Takashi Inui, Atsushi Kamiya, Akira Sawa, Tadayoshi Takeuchi

研究成果: Article査読

38 被引用数 (Scopus)

抄録

In addition to its role in DNA repair, nuclear poly(ADP-ribose) polymerase-1 (PARP-1) mediates brain damage when it is over-activated by oxidative/nitrosative stress. Nonetheless, it remains unclear how PARP-1 is activated in neuropathological contexts. Here we report that PARP-1 interacts with a pool of glyceradehyde-3-phosphate dehydrogenase (GAPDH) that translocates into the nucleus under oxidative/nitrosative stress both in vitro and in vivo. A well conserved amino acid at the N terminus of GAPDH determines its protein binding with PARP-1. Wild-type (WT) but not mutant GAPDH, that lacks the ability to bind PARP-1, can promote PARP-1 activation. Importantly, disrupting this interaction significantly diminishes PARP-1 overactivation and protects against both brain damage and neurological deficits induced by middle cerebral artery occlusion/reperfusion in a rat stroke model. Together, these findings suggest that nuclear GAPDH is a key regulator of PARP-1 activity, and its signaling underlies the pathology of oxidative/nitrosative stress-induced brain damage including stroke.

本文言語English
ページ(範囲)14493-14503
ページ数11
ジャーナルJournal of Biological Chemistry
290
23
DOI
出版ステータスPublished - 05-06-2015
外部発表はい

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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