The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation

Yeates, Eniola Funmilayo Aduke; Tesco, Giuseppina

doi:10.1074/jbc.m116.718023

Cited by 59 publications

(42 citation statements)

References 71 publications

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“…These increases accord with the elevated levels of sAPPb and BACE1 (b-site amyloid precursor protein cleaving enzyme 1) activity in AD (27)(28)(29)(30). Increased BACE1 activity is known to arise in various ways in AD (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). For example, shifts in the localization of BACE1 and APP, which are further promoted by ApoE4 overexpression (43) and bridging integrator 1 loss of function (44), bring these 2 proteins together within acidic microdomains (45).…”

Section: Endosomopathy: the Earliest Ad Pathobiology And The Key To Ementioning

confidence: 84%

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

2017

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Abnormalities of the endosomal-lysosomal network (ELN) are a signature feature of Alzheimer's disease (AD). These include the earliest known cytopathology that is specific to AD and that affects endosomes and induces the progressive failure of lysosomes, each of which are directly linked by distinct mechanisms to neurodegeneration. The origins of ELN dysfunction and β-amyloidogenesis closely overlap, which reflects their common genetic basis, the established early involvement of endosomes and lysosomes in amyloid precursor protein (APP) processing and clearance, and the pathologic effect of certain APP metabolites on ELN functions. Genes that promote β-amyloidogenesis in AD (APP, PSEN1/2, and APOE4) have primary effects on ELN function. The importance of primary ELN dysfunction to pathogenesis is underscored by the mutations in more than 35 ELN-related genes that, thus far, are known to cause familial neurodegenerative diseases even though different pathogenic proteins may be involved. In this article, I discuss growing evidence that implicates AD gene-driven ELN disruptions as not only the antecedent pathobiology that underlies β-amyloidogenesis but also as the essential partner with APP and its metabolites that drive the development of AD, including tauopathy, synaptic dysfunction, and neurodegeneration. The striking amelioration of diverse deficits in animal AD models by remediating ELN dysfunction further supports a need to integrate APP and ELN relationships, including the role of amyloid-β, into a broader conceptual framework of how AD arises, progresses, and may be effectively therapeutically targeted.-Nixon, R. A. Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease.

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Section: Endosomopathy: the Earliest Ad Pathobiology And The Key To Ementioning

confidence: 84%

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

2017

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“…BACE1 is ubiquitinated at a single lysine in the C terminus, leading to accumulation of BACE1 in endosomes and an increase in APP processing (62). A␤ levels can be reduced by depletion of the deubiquitinase ubiquitinspecific protease 8 (USP8), which increases BACE1 ubiquitination and leads to a redistribution of BACE1 away from Rab11positive recycling endosomes (63). These studies underline the effect that ubiquitin regulators can have on A␤ production and the need for identification of ubiquitin ligases and deubiquitinases affecting APP itself.…”

Section: Discussionmentioning

confidence: 97%

Disruption of amyloid precursor protein ubiquitination selectively increases amyloid β (Aβ) 40 levels via presenilin 2-mediated cleavage

Williamson¹,

Laulagnier

Miranda

et al. 2017

Journal of Biological Chemistry

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Amyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid β (Aβ) peptide, derived from cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The endosome is increasingly recognized as an important crossroad for APP and these secretases, with major implications for APP processing and amyloidogenesis. Among various post-translational modifications affecting APP accumulation, ubiquitination of cytodomain lysines may represent a key signal controlling APP endosomal sorting. Here, we show that substitution of APP C-terminal lysines with arginine disrupts APP ubiquitination and that an increase in the number of substituted lysines tends to increase APP metabolism. An APP mutant lacking all C-terminal lysines underwent the most pronounced increase in processing, leading to accumulation of both secreted and intracellular Aβ40. Artificial APP ubiquitination with rapalog-mediated proximity inducers reduced Aβ40 generation. A lack of APP C-terminal lysines caused APP redistribution from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with a subsequent decrease in APP C-terminal fragment (CTF) content in secreted exosomes, but had minimal effects on APP lysosomal degradation. Both the increases in secreted and intracellular Aβ40 were abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared with PSEN1. Our findings demonstrate that ubiquitin can act as a signal at five cytodomain-located lysines for endosomal sorting of APP. They further suggest that disruption of APP endosomal sorting reduces its sequestration in ILVs and results in PSEN2-mediated processing of a larger pool of APP-CTF on the endosomal membrane.

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“…Although many studies have been focused on BACE1 trafficking and turnover in non-neuronal cell types (16,45,46) or neuron-derived cell lines (12,15,47,48), its relevance to BACE1 long distance axonal transport and its retention and cleavage of APP in distal axons remains unknown. This study examined, for the first time, the autophagy-mediated regulation of BACE1 trafficking to lysosomes for degradation in WT and AD-related neurons.…”

Section: Discussionmentioning

confidence: 99%

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

Feng¹,

Tammineni²,

Agrawal

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartino ␤-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal ␤-secretase for amyloid-␤ generation and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation. Here, we report that induction of neuronal autophagy enhances BACE1 turnover, which is suppressed by lysosomal inhibition. A significant portion of BACE1 is recruited to the autophagy pathway and co-migrates robustly with autophagic vacuoles along axons. Moreover, we reveal that autophagic vacuole-associated BACE1 is accumulated in the distal axon of Alzheimer's disease-related mutant human APP transgenic neurons and mouse brains. Inducing autophagy in mutant human APP neurons augments autophagic retention of BACE1 in distal axons, leading to enhanced ␤-cleavage of APP. This phenotype can be reversed by Snapin-enhanced retrograde transport, which facilitates BACE1 trafficking to lysosomes for degradation. Therefore, our study provides new insights into autophagy-mediated regulation of BACE1 turnover and APP processing, thus building a foundation for future development of potential Alzheimer's disease therapeutic strategies.Accumulation of senile plaques is a pathological hallmark of Alzheimer's disease (AD).3 Amyloid-␤ (A␤) peptide is the main constituent of senile plaques and is derived from a sequential proteolysis of amyloid precursor protein (APP) by ␤-and ␥-secretases. ␤-Secretase is the initial and rate-limiting enzyme of this process (1-4). ␤-Site APP-cleaving enzyme 1 (BACE1) is the major neuronal ␤-secretase for A␤ generation (1-4). BACE1 levels increase with age (5) and are elevated in AD patient brains (6), thereby making BACE1 a prime target for therapeutic intervention (7-9). BACE1 is synthesized in the endoplasmic reticulum and then delivered to the cell surface from the trans-Golgi network (TGN). Mature BACE1 traffics to endosomes via internalization from the plasma membrane or directly from the TGN (3, 10 -12). The endosomal compartments (especially late endosomes (LEs) or multivesicular bodies) provide an acidic environment that is crucial for optimal ␤-secretase activity (10, 13-17), whereas BACE1 is ultimately degraded within lysosomes (15, 18 -20). Given that mature lysosomes are mainly located in the soma of neurons (21-24), proper retrograde transport of LE-loaded BACE1 is critical for the trafficking of BACE1 to lysosomes for turnover (20).Autophagy is the major cellular degradation pathway for long-lived proteins and damaged organelles (25-28). Altered autophagy has been linked to several major age-related neurodegenerative diseases, including AD (27). Recent studies established that autophagosomes are continuously...

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The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation

Cited by 59 publications

References 71 publications

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

Disruption of amyloid precursor protein ubiquitination selectively increases amyloid β (Aβ) 40 levels via presenilin 2-mediated cleavage

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

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