RGD Reference Report - Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. - Rat Genome Database

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

Authors: Liu, Zhixue  Jang, Sung-Wuk  Liu, Xia  Cheng, Dongmei  Peng, Junmin  Yepes, Manuel  Li, Xiao-jiang  Matthews, Steve  Watts, Colin  Asano, Masahide  Hara-Nishimura, Ikuko  Luo, Hongbo R  Ye, Keqiang 
Citation: Liu Z, etal., Mol Cell. 2008 Mar 28;29(6):665-78. doi: 10.1016/j.molcel.2008.02.017.
RGD ID: 13514088
Pubmed: PMID:18374643   (View Abstract at PubMed)
PMCID: PMC2819101   (View Article at PubMed Central)
DOI: DOI:10.1016/j.molcel.2008.02.017   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
LgmnRatcysteine-type endopeptidase activity enablesIMP PMID:18374643ARUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Lgmn  (legumain)


Additional Information