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

Zhixue Liu, Sung-Wuk Jang, Xia Liu, Dongmei Cheng, Junmin Peng, Manuel Yepes, Xiao-jiang Li, Steve Matthews, Colin Watts, Masahicle Asano, Ikuko Hara-Nishimura, Hongbo R. Luo, Keqiang Ye

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    88 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)665-678
    Number of pages14
    JournalMolecular Cell
    Volume29
    Issue number6
    DOIs
    Publication statusPublished - 28 Mar 2008

    Keywords

    • ACUTE UNDIFFERENTIATED LEUKEMIA
    • ASSEMBLY PROTEIN SET
    • GRANZYME-A
    • CELL-DEATH
    • INTRACELLULAR ACIDIFICATION
    • ANTIGEN PRESENTATION
    • NEURONAL APOPTOSIS
    • ENERGY-METABOLISM
    • NUCLEAR GTPASE
    • COMPLEX

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