The Ubiquitin E3 Ligase Nedd4 Regulates the Expression and Amyloid-β Peptide Export Activity of P-Glycoprotein.
ATP Binding Cassette Transporter, Subfamily B
/ metabolism
Amyloid beta-Protein Precursor
/ genetics
Animals
Biological Transport
CHO Cells
Cloning, Molecular
/ methods
Cricetulus
Fluoresceins
/ metabolism
Gene Expression Regulation
Gene Knockdown Techniques
Humans
Nedd4 Ubiquitin Protein Ligases
/ genetics
Ubiquitination
ABCB1
Nedd4
P-glycoprotein
amyloid-beta
ubiquitin E3 ligase
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
18 Jan 2022
18 Jan 2022
Historique:
received:
30
12
2021
revised:
12
01
2022
accepted:
16
01
2022
entrez:
15
2
2022
pubmed:
16
2
2022
medline:
9
3
2022
Statut:
epublish
Résumé
The ATP-binding cassette transporter, P-glycoprotein (P-gp), has been demonstrated to facilitate the clearance of amyloid-beta (Aβ) peptides, exporting the neurotoxic entity out of neurons and out of the brain via the blood-brain barrier. However, its expression and function diminish with age and in Alzheimer's disease. P-gp is known to undergo ubiquitination, a post-translational modification that results in internalisation and/or degradation of the protein. NEDD4-1 is a ubiquitin E3 ligase that has previously been shown to ubiquitinate P-gp and reduce its cell surface expression. However, whether this effect translates into altered P-gp activity remains to be determined. siRNA was used to knockdown the expression of Nedd4 in CHO-APP cells. Western blot analysis confirmed that absence of Nedd4 was associated with increased P-gp protein expression. This was accompanied by increased transport activity, as shown by export of the P-gp substrate calcein-AM, as well as enhanced secretion of Aβ peptides, as shown by ELISA. These results implicate Nedd4 in the regulation of P-gp, and highlight a potential approach for restoring or augmenting P-gp expression and function to facilitate Aβ clearance from the brain.
Identifiants
pubmed: 35162941
pii: ijms23031019
doi: 10.3390/ijms23031019
pmc: PMC8834788
pii:
doi:
Substances chimiques
ABCB1 protein, human
0
APP protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
Amyloid beta-Protein Precursor
0
Fluoresceins
0
calcein AM
148504-34-1
Nedd4 Ubiquitin Protein Ligases
EC 2.3.2.26
Nedd4 protein, human
EC 2.3.2.26
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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