HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation

• Published in: The Journal of biological chemistry 2007-09, Vol.282 (38), p.28285-28295
• Main Authors: Huttunen, Henri J., Guénette, Suzanne Y., Peach, Camilla, Greco, Christopher, Xia, Weiming, Kim, Doo Yeon, Barren, Cory, Tanzi, Rudolph E., Kovacs, Dora M.
• Format: Article
• Language: English
• Subjects: Amyloid - metabolism; Animals; Brain - metabolism; CHO Cells; Cricetinae; Cricetulus; Cytosol - metabolism; Endoplasmic Reticulum - metabolism; High-Temperature Requirement A Serine Peptidase 2; Humans; Membrane Proteins - biosynthesis; Mice; Mitochondrial Proteins - metabolism; Mitochondrial Proteins - physiology; Protein Structure, Tertiary; Serine Endopeptidases - metabolism; Serine Endopeptidases - physiology; Subcellular Fractions - metabolism; Vesicular Transport Proteins - physiology
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M702951200

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.