Endoplasmic reticulum-localized amyloid beta-peptide is degraded in the cytosol by two distinct degradation pathways

Traffic. 2004 Feb;5(2):89-101. doi: 10.1111/j.1600-0854.2004.00159.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / cytology
  • Brain / metabolism
  • CHO Cells
  • Cricetinae
  • Cysteine Endopeptidases / metabolism
  • Cytoplasm / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • HeLa Cells
  • Humans
  • Insulysin / metabolism
  • Membrane Proteins / metabolism
  • Microsomes / metabolism
  • Molecular Sequence Data
  • Multienzyme Complexes / metabolism
  • Peptide Fragments / metabolism*
  • Proteasome Endopeptidase Complex
  • Protein Sorting Signals
  • Protein Transport / physiology
  • RNA Interference
  • SEC Translocation Channels
  • Swine


  • Amyloid beta-Peptides
  • Membrane Proteins
  • Multienzyme Complexes
  • Peptide Fragments
  • Protein Sorting Signals
  • SEC Translocation Channels
  • amyloid beta-protein (1-42)
  • Adenosine Triphosphate
  • Cysteine Endopeptidases
  • Insulysin
  • Proteasome Endopeptidase Complex