Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) Polymerase-1 Activation during Oxidative/Nitrosative Stress in Stroke

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

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290(23): 14493-14503.

DOI：10.1074/jbc.M114.635607

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.

• 出版日期2015-6-5