HtrA2 regulates beta-amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation.
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.
Neurobiology of Disease Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Henri J
HJ
Huttunen
Suzanne Y
SY
Guénette
Camilla
C
Peach
Christopher
C
Greco
Weiming
W
Xia
Doo Yeon
DY
Kim
Cory
C
Barren
Rudolph E
RE
Tanzi
Dora M
DM
Kovacs
D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000502:physiology
D000682:Amyloid; C487709:DERL1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C512739:SEC23A protein, human; D033921:Vesicular Transport Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse