Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

D, Del Prete; Rice, Richard C.; Rajadhyaksha, Anjali M.; D’Adamio, Luciano

doi:10.1074/jbc.m116.733626

Cited by 62 publications

(37 citation statements)

References 143 publications

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“…HRD1 interacts with APP through its Proline-rich region, and this interaction reduces Aβ generation through promoting APP ubiquitination and degradation (Kaneko et al, 2010). In addition, APP can bind to ubiquitin E3 ligases Stub1 and CRL4 CRBN through the APP cytosolic region (ACR; Del Prete et al, 2016). ACR promotes the ubiquitination of several presynaptic proteins and regulates neurotransmitter release (Del Prete et al, 2016).…”

Section: Dysregulation Of Ubiquitination In Neurodegenerative Diseasesmentioning

confidence: 99%

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Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Zheng

Huang

Zhang

et al. 2016

Front. Aging Neurosci.

244

171

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The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

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Section: Dysregulation Of Ubiquitination In Neurodegenerative Diseasesmentioning

confidence: 99%

“…In addition, APP can bind to ubiquitin E3 ligases Stub1 and CRL4 CRBN through the APP cytosolic region (ACR; Del Prete et al, 2016). ACR promotes the ubiquitination of several presynaptic proteins and regulates neurotransmitter release (Del Prete et al, 2016). …”

Section: Dysregulation Of Ubiquitination In Neurodegenerative Diseasesmentioning

confidence: 99%

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Zheng

Huang

Zhang

et al. 2016

Front. Aging Neurosci.

244

171

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“…CUL4B is a known E3 ligase that directly regulates protein levels through ubiquitination (30,42). To delineate how CUL4B regulates expression of Cav1.2 and AC6, we examined Cav1.2 and AC6 ubiquitination in CUL4B-overexpressing and control TGP52 cells ( Figure 6A).…”

Section: Cul4b Ablation In Pancreatic δ Cells Other Than β Cells Causmentioning

confidence: 99%

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Cui

Yang

et al. 2017

Journal of Clinical Investigation

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Figure 1. CUL4B deficiency in pancreatic δ cells impairs glucose metabolism. (A and B)Western blots and quantitative data for CUL4A and CUL4B protein levels in islets from 12-week-old diabetic db/db mice and their heterozygous littermates (db/+). n = 6 mice per group. Representative Western blots from at least 3 independent experiments are shown. (C) Immunostaining for CUL4B (green) and somatostatin (SST, red) in pancreatic sections from db/db and db/+ mice. Scale bar: 100 μm. n = 6 mice per group; 4-7 random areas were selected from each islet section, and 10 sections were randomly selected from each mouse. Insulininduced decreases in blood glucose levels were significantly lower in Sst-Cre +/-Cul4b fl/Y mice than in their WT littermates, and they did not return to baseline levels at the 2-hour time point, whereas the levels of their WT littermates did (n = 9-11). *P < 0.05; **P < 0.01; ***P < 0.001. db/db mice were compared with their db/+ littermates, and Sst-Cre +/-Cul4b fl/Y mice were compared with their WT littermates. Error bars in F represent mean ± SD; other bars represent mean ± SEM. All data were analyzed using 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 6 3 3 jci.orgVolume 127 Number 7 July 2017mental Figure 1E). Immunofluorescence also showed no significant differences in islet or β or δ cell numbers between +/-mice, the knockout mice exhibited increased glucose levels after 2 hours of feeding following a 16-hour fast ( Figure 1G). Accordingly, during a glucose tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice were 33% and 30% higher at 30 minutes and 120 minutes, respectively, than those of the control group consisting of both Sst-Cre +/-and Cul4b fl/Y mice ( Figure 1H). In addition, during the insulin tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice unexpectedly decreased more dramatically and rapidly than those of the Sst-Cre +/-control mice in response to insulin stimulation ( Figure 1I). Insulin and somatostatin content as well as kidney, brain, heart, liver, and stomach weights were not found to be significantly different between the mice was 140% and 40% higher than that of Sst-Cre +/-mice at 5 minutes and 60 minutes, respectively ( Figure 2H). In contrast to the results found for the Sst-Cre +/-Cul4b fl/Y mice, CUL4B defistrated that CRL4 ubiquitinates WD repeat-containing protein 5 (WDR5), a core subunit of H3K4 methyltransferase complexes, for degradation in the nucleus, thereby promoting increased H3K4 methylation levels (30). However, whether CUL4B or its E3 ligase complex CRL4B-PRC2 participates in the functioning or development of Langerhans islets has not been studied. In this study, we found that CUL4B expression levels are decreased in db/db mice. Therefore, we crossed mice expressing Cre under the insulin II promotor (Ins2-Cre) and mice expressing Cre under the somatostatin promoter (Sst-Cre) with Cul4b fl/fl mice to characterize CUL4B functions in specific cell types of the islet circuit. Although In...

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“…Ubiquitin is a 76-amino acid peptide that is covalently attached to lysine residues of a protein cargo via sequential enzymatic reactions of E1, E2 and E3 ubiquitin ligases (35). The E3 ubiquitin ligase(s) specific for APP remains uncertain, but some studies suggest promising candidates (36,37), and a recent GWAS of Caribbean Hispanics identified F-box/leucine rich-repeat protein 7 (FBXL7), a subunit of an E3 ligase, to be associated with LOAD (38). Several reports identify ubiquitination sites on APP (37, 39, 40) or report alterations in A␤ levels due to changes in APP ubiquiti-nation (7,36,41), but they do not investigate in depth of the mechanism underlying this phenomenon or the downstream effects of reduced ubiquitination.…”

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confidence: 99%

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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Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

Cited by 62 publications

References 143 publications

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

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

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