The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation.
The β-site amyloid precursor protein-cleaving enzyme (BACE1) is the rate-limiting enzyme in the production of amyloid-β, the toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that that depletion of the trafficking molecule Golgi-localized γ-ear-containing ARF-binding protein 3 (GGA3) results in increased BACE1 levels and activity because of impaired lysosomal degradation. We also determined that GGA3 regulation of BACE1 levels requires its ability to bind ubiquitin. Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization. Ubiquitin conjugation is a reversible process mediated by deubiquitinating enzymes. The ubiquitin-specific peptidase 8 (USP8), an endosome-associated deubiquitinating enzyme, regulates the ubiquitination, trafficking, and lysosomal degradation of several plasma membrane proteins. Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes. We also found that decreased BACE1 protein levels were accompanied by a decrease in BACE1-mediated amyloid precursor protein cleavage and amyloid-β levels. Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. These studies suggest that therapies able to accelerate BACE1 degradation (e.g. by increasing BACE1 ubiquitination) may represent a potential treatment for Alzheimer disease.
From the Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
Eniola Funmilayo Aduke
EF
Yeates
From the Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111 giuseppina.tesco@Tufts.edu.
Giuseppina
G
Tesco
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C545487:APP protein, human; D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; D056827:Endosomal Sorting Complexes Required for Transport; C407306:GGA adaptor proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer disease; amyloid-β (AB); deubiquitylation (deubiquitination); lysosome; protein degradation; trafficking; β-secretase 1 (BACE1)