title: Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase.
abstract: 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, 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.
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors: Zhixue
authors: Z
authors: Liu
authors: Sung-Wuk
authors: SW
authors: Jang
authors: Xia
authors: X
authors: Liu
authors: Dongmei
authors: D
authors: Cheng
authors: Junmin
authors: J
authors: Peng
authors: Manuel
authors: M
authors: Yepes
authors: Xiao-jiang
authors: XJ
authors: Li
authors: Steve
authors: S
authors: Matthews
authors: Colin
authors: C
authors: Watts
authors: Masahide
authors: M
authors: Asano
authors: Ikuko
authors: I
authors: Hara-Nishimura
authors: Hongbo R
authors: HR
authors: Luo
authors: Keqiang
authors: K
authors: Ye
mesh_terms: D000818:Animals; D001215:Asparaginase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D053804:Granzymes / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology; D056488:Histone Chaperones; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007511:Ischemia / Q000201:enzymology / Q000503:physiopathology; D007608:Kainic Acid / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D016716:PC12 Cells; D014176:Protein Biosynthesis; D051381:Rats; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D056488:Histone Chaperones; D018696:Neuroprotective Agents; C513473:SET protein, human; D014157:Transcription Factors; D053804:Granzymes; D001215:Asparaginase; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins; D007608:Kainic Acid