Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase.
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.
Liu
Zhixue
Z
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Jang
Sung-Wuk
SW
Liu
Xia
X
Cheng
Dongmei
D
Peng
Junmin
J
Yepes
Manuel
M
Li
Xiao-jiang
XJ
Matthews
Steve
S
Watts
Colin
C
Asano
Masahide
M
Hara-Nishimura
Ikuko
I
Luo
Hongbo R
HR
Ye
Keqiang
K
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
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