HtrA2 regulates β-amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation

Henri J. Huttunen, Suzanne Y. Guénette, Camilla Peach, Christopher Greco, Weiming Xia, Yeon Kim Doo, Cory Barren, Rudolph E. Tanzi, Dora M. Kovacs

    Research output: Contribution to journalArticlepeer-review

    66 Scopus citations

    Abstract

    Alzheimer disease-associated β-amyloid peptide is generated from its precursor protein APP. By using the yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as a protein binding to the N-terminal cysteinerich region of APP. HtrA2 coimmunoprecipitates exclusively with immature APP from cell lysates as well as mouse brain extracts and degrades APP in vitro. A subpopulation of HtrA2 localizes to the cytosolic side of the endoplasmic reticulum (ER) membrane where it contributes to ER-associated degradation of APP together with the proteasome. Inhibition of the proteasome results in accumulation of retrotranslocated forms of APP and increased association of APP with HtrA2 and Derlin-1 in microsomal membranes. In cells lacking HtrA2, APP holoprotein is stabilized and accumulates in the early secretory pathway correlating with elevated levels of APP C-terminal fragments and increased Aβ secretion. Inhibition of ER-associated degradation (either HtrA2 or proteasome) promotes binding of APP to the COPII protein Sec23 suggesting enhanced trafficking of APP out of the ER. Based on these results we suggest a novel function for HtrA2 as a regulator of APP metabolism through ER-associated degradation.

    Original languageEnglish (US)
    Pages (from-to)28285-28295
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume282
    Issue number38
    DOIs
    StatePublished - Sep 21 2007

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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