Calsyntenin-3 interacts with the sodium-dependent vitamin C transporter-2 to regulate vitamin C uptake

Ascorbic acid (AA) uptake in neurons occurs via a Na+-dependent carrier-mediated process mediated by the sodium-dependent vitamin C transporter-2 (SVCT2). Relatively little information is available concerning the network of interacting proteins that support human (h)SVCT2 trafficking and cell surfac...

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Bibliographic Details
Published in:International journal of biological macromolecules 2021-12, Vol.192, p.1178-1184
Main Authors: Subramanian, Veedamali S., Teafatiller, Trevor, Vidal, Janielle, Gunaratne, Gihan S., Rodriguez-Ortiz, Carlos J., Kitazawa, Masashi, Marchant, Jonathan S.
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animals
Ascorbic Acid - metabolism
Calcium-Binding Proteins - metabolism
Cell Line
CLSTN3
Gene Expression
Hippocampus - metabolism
Humans
Interactor
Membrane Proteins - metabolism
Mice
Neurons - metabolism
Protein Binding
Sodium-Coupled Vitamin C Transporters - metabolism
SVCT2
Transport
Two-Hybrid System Techniques
Vitamin C
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Summary:Ascorbic acid (AA) uptake in neurons occurs via a Na+-dependent carrier-mediated process mediated by the sodium-dependent vitamin C transporter-2 (SVCT2). Relatively little information is available concerning the network of interacting proteins that support human (h)SVCT2 trafficking and cell surface expression in neuronal cells. Here we identified the synaptogenic adhesion protein, calsyntenin-3 (CLSTN3) as an hSVCT2 interacting protein from yeast two-hybrid (Y2H) screening of a human adult brain cDNA library. This interaction was confirmed by co-immunoprecipitation, mammalian two-hybrid (M2H), and co-localization in human cell lines. Co-expression of hCLSTN3 with hSVCT2 in SH-SY5Y cells led to a marked increase in AA uptake. Reciprocally, siRNA targeting hCLSTN3 inhibited AA uptake. In the J20 mouse model of Alzheimer's disease (AD), mouse (m)SVCT2 and mCLSTN3 expression levels in hippocampus were decreased. Similarly, expression levels of hSVCT2 and hCLSTN3 were markedly decreased in hippocampal samples from AD patients. These findings establish CLSTN3 as a novel hSVCT2 interactor in neuronal cells with potential pathophysiological significance. •CLSTN3 identified as an SVCT2 interacting protein from a human brain cDNA library•Co-expression of CLSTN3 with SVCT2 led to a marked increase in vitamin C uptake.•Expression levels of CLSTN3 and SVCT2 were markedly decreased in AD brain.•CLSTN3 may contribute to impaired vitamin C homeostasis in AD brain.
ISSN:0141-8130
1879-0003
DOI:10.1016/j.ijbiomac.2021.10.058