HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation
| Autor: | Henri J. Huttunen, Doo Yeon Kim, Cory Barren, Camilla Peach, Suzanne Y. Guénette, Weiming Xia, Rudolph E. Tanzi, Christopher Greco, Dora M. Kovacs |
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| Rok vydání: | 2007 |
| Předmět: |
Amyloid
Vesicular Transport Proteins CHO Cells Endoplasmic-reticulum-associated protein degradation Endoplasmic Reticulum Biochemistry Mitochondrial Proteins Mice Cricetulus Cytosol Cricetinae mental disorders Animals Humans Secretion Molecular Biology COPII Secretory pathway Chemistry Endoplasmic reticulum Serine Endopeptidases Brain Membrane Proteins Cell Biology High-Temperature Requirement A Serine Peptidase 2 Protein Structure Tertiary Proteasome Microsome Subcellular Fractions |
| Zdroj: | Journal of Biological Chemistry. 282:28285-28295 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m702951200 |
| Popis: | Alzheimer disease-associated beta-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 Abeta 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. |
| Databáze: | OpenAIRE |
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