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

April 16th, 2015 by Nakajima, H., Kubo, T., Ihara, H., Hikida, T., Danjo, T., Nakatsuji, M., Shahani, N., Itakura, M., Ono, Y., Azuma, Y.-T., Inui, T., Kamiya, A., Sawa, A., Takeuchi, T.

In addition to its role in DNA repair, nuclear poly(ADP-ribose) polymerase-1 (PARP-1) mediates brain damage when it is overactivated 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 (MCAO)/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.
  • Posted in Journal of Biological Chemistry, Publications
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