Neuroprotective Actions of PIKE-L by Inhibition of SET Proteolytic Degradation by Asparagine Endopeptidase (AEP)

• Type of Material: Article
• Authors: Zhixue Liu, Emory University; Sung-Wuk Jang, Emory University; Xia Liu, Emory University; Dongmei Cheng, Emory University; Junmin Peng, Emory University; Manuel Yepes, Emory University; Xiao-Jiang Li, Emory University; Steve Matthews, Emory University; Colin Watts, Emory University; Masahide Asano, Kanazawa University; Ikuko Hara-Nishimura, Kanazawa University; Hongbo R. Luo, Children's Hospital Boston; Keqiang Ye, Emory University
• Language: English
• Date: 2008-03-28
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 Elsevier Inc. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016%2Fj.molcel.2008.02.017
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 29
• Issue: 6
• Start Page: 665
• End Page: 665
• Grant/Funding Information: This work is supported by grants from National Institute of Health RO1, NS045627 to K.Y. and NS-49478 to M.Y.
• Research Categories: Biology, Molecular; Biology, Cell

Abstract

Summary Ischemia and seizure cause excessive neuronal excitation that is associated with brain acidosis and neuronal cell death. However, the molecular mechanism of acidification-triggered neuronal injury is incompletely understood. Here, we show that Asparagine Endopeptidase (AEP) is activated under acidic condition and cuts SET, an inhibitor of Dnase, and triggers DNA damage in brain, which is inhibited by PIKE-L. SET, a substrate of caspases, was cleaved by acidic cytosolic extract independent of caspase activation. Fractionation of the acidic cellular extract yielded AEP that is required for SET cleavage. We found that kainate provoked AEP activation and SET cleavage at N175, triggering DNA nicking in wild-type but not AEP-null mice. PIKE-L strongly bound SET and prevented its degradation by AEP, leading to resistance of neuronal cell death. Moreover, AEP also mediated stroke-provoked SET cleavage and cell death in brain. Thus, AEP might be one of the proteinases activated by acidosis triggering neuronal injury during neuroexcitotoxicity or ischemia.