Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase

Mol Cell. 2008 Mar 28;29(6):665-78. doi: 10.1016/j.molcel.2008.02.017.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Asparaginase / deficiency
  • Asparaginase / genetics
  • Asparaginase / metabolism*
  • Cell Death
  • Chromosomal Proteins, Non-Histone / antagonists & inhibitors*
  • DNA-Binding Proteins
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins / metabolism*
  • Granzymes / metabolism
  • Hippocampus / enzymology
  • Histone Chaperones
  • Humans
  • Hydrogen-Ion Concentration
  • Ischemia / enzymology
  • Ischemia / physiopathology
  • Kainic Acid / pharmacology
  • Kinetics
  • Mice
  • Mice, Knockout
  • Neurons / pathology
  • Neuroprotective Agents / metabolism
  • PC12 Cells
  • Protein Biosynthesis
  • Rats
  • T-Lymphocytes, Cytotoxic / enzymology
  • Transcription Factors / antagonists & inhibitors*
  • Transcription, Genetic


  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • GTPase-Activating Proteins
  • Histone Chaperones
  • Neuroprotective Agents
  • SET protein, human
  • Transcription Factors
  • Granzymes
  • Asparaginase
  • AGAP2 protein, human
  • GTP-Binding Proteins
  • Kainic Acid