Endoplasmic Reticulum-Localized Amyloid β-Peptide is Degraded in the Cytosol by Two Distinct Degradation Pathways

Authors

  • Anton Schmitz,

    Corresponding author
    1. Institut für Zellbiologie, Rheinische Friedrich-Wilhelms-Universität, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany,
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  • Andrea Schneider,

    1. Institut für Zellbiologie, Rheinische Friedrich-Wilhelms-Universität, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany,
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  • Markus P. Kummer,

    1. Institut für Zellbiologie, Rheinische Friedrich-Wilhelms-Universität, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany,
    2. Present address: UCSD, Department of Neurosciences, La Jolla, CA 92093–0691
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  • Volker Herzog

    1. Institut für Zellbiologie, Rheinische Friedrich-Wilhelms-Universität, Ulrich-Haberland-Str. 61a, 53121 Bonn, Germany,
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*Anton Schmitz, anton.schmitz@ uni-bonn.de

Abstract

The paradigm of endoplasmic reticulum (ER)-associated degradation (ERAD) holds that misfolded secretory and membrane proteins are translocated back to the cytosol and degraded by the proteasome in a coupled process. Analyzing the degradation of ER-localized amyloid β-peptide (Aβ), we found a divergence from this general model. Cell-free reconstitution of the export in biosynthetically loaded ER-derived brain microsomes showed that the export was mediated by the Sec61p complex and required a cytosolic factor but was independent of ATP. In contrast to the ERAD substrates known so far, the exported Aβ was degraded by both, a proteasome-dependent and a proteasome-independent pathway. RNA interference experiments in Aβ-transfected cells identified the protease of the proteasome-independent pathway as insulin-degrading enzyme (IDE). The IDE-mediated clearance mechanism for ER-localized Aβ represents an as yet unknown type of ERAD which is not entirely dependent on the proteasome.

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