Endoplasmic reticulum-localized amyloid beta-peptide is degraded in the cytosol by two distinct degradation pathways.
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 beta-peptide (Abeta), 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 Abeta was degraded by both, a proteasome-dependent and a proteasome-independent pathway. RNA interference experiments in Abeta-transfected cells identified the protease of the proteasome-independent pathway as insulin-degrading enzyme (IDE). The IDE-mediated clearance mechanism for ER-localized Abeta represents an as yet unknown type of ERAD which is not entirely dependent on the proteasome.
Schmitz
Anton
A
Institut für Zellbiologie, Rheinische Friedrich-Wilhelms-Universität, Ulrich-Haberland-Str 61a, 53121 Bonn, Germany. anton.schmitz@uni-bonn.de
Schneider
Andrea
A
Kummer
Markus P
MP
Herzog
Volker
V
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007339:Insulysin / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D021382:Protein Sorting Signals; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference; D000069816:SEC Translocation Channels; D013552:Swine
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D021382:Protein Sorting Signals; D000069816:SEC Translocation Channels; C075222:amyloid beta-protein (1-42); D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases; D007339:Insulysin; D046988:Proteasome Endopeptidase Complex