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O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains

Like protein phosphorylation, O-GlcNAcylation is a common post-translational protein modification. We already reported that O-GlcNAcylation of amyloid precursor protein (APP) in response to insulin signaling reduces neurotoxic amyloid-β (Aβ) production via inhibition of APP endocytosis. Internalized...

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Autores principales: Kwon, Oh-Hoon, Cho, Yoon Young, Lee, Jung Hee, Chung, Sungkwon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704492/
https://www.ncbi.nlm.nih.gov/pubmed/34940409
http://dx.doi.org/10.3390/membranes11120909
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author Kwon, Oh-Hoon
Cho, Yoon Young
Lee, Jung Hee
Chung, Sungkwon
author_facet Kwon, Oh-Hoon
Cho, Yoon Young
Lee, Jung Hee
Chung, Sungkwon
author_sort Kwon, Oh-Hoon
collection PubMed
description Like protein phosphorylation, O-GlcNAcylation is a common post-translational protein modification. We already reported that O-GlcNAcylation of amyloid precursor protein (APP) in response to insulin signaling reduces neurotoxic amyloid-β (Aβ) production via inhibition of APP endocytosis. Internalized APP is delivered to endosomes and lysosomes where Aβ is produced. However, the molecular mechanism involved in the effect of APP O-GlcNAcylation on APP trafficking remains unknown. To investigate the relationship between APP O-GlcNAcylation and APP endocytosis, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing APP and BACE1, and cultured rat hippocampal neurons. The present study showed that APP O-GlcNAcylation translocated APP from lipid raft to non-raft microdomains in the plasma membrane by using immunocytochemistry and discontinuous sucrose gradients method. By using the biotinylation method, we also found that APP preferentially underwent endocytosis from lipid rafts and that the amount of internalized APP from lipid rafts was specifically reduced by O-GlcNAcylation. These results indicate that O-GlcNAcylation can regulate lipid raft-dependent APP endocytosis via translocation of APP into non-raft microdomains. Our findings showed a new functional role of O-GlcNAcylation for the regulation of APP trafficking, offering new mechanistic insight for Aβ production.
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spelling pubmed-87044922021-12-25 O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains Kwon, Oh-Hoon Cho, Yoon Young Lee, Jung Hee Chung, Sungkwon Membranes (Basel) Article Like protein phosphorylation, O-GlcNAcylation is a common post-translational protein modification. We already reported that O-GlcNAcylation of amyloid precursor protein (APP) in response to insulin signaling reduces neurotoxic amyloid-β (Aβ) production via inhibition of APP endocytosis. Internalized APP is delivered to endosomes and lysosomes where Aβ is produced. However, the molecular mechanism involved in the effect of APP O-GlcNAcylation on APP trafficking remains unknown. To investigate the relationship between APP O-GlcNAcylation and APP endocytosis, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing APP and BACE1, and cultured rat hippocampal neurons. The present study showed that APP O-GlcNAcylation translocated APP from lipid raft to non-raft microdomains in the plasma membrane by using immunocytochemistry and discontinuous sucrose gradients method. By using the biotinylation method, we also found that APP preferentially underwent endocytosis from lipid rafts and that the amount of internalized APP from lipid rafts was specifically reduced by O-GlcNAcylation. These results indicate that O-GlcNAcylation can regulate lipid raft-dependent APP endocytosis via translocation of APP into non-raft microdomains. Our findings showed a new functional role of O-GlcNAcylation for the regulation of APP trafficking, offering new mechanistic insight for Aβ production. MDPI 2021-11-23 /pmc/articles/PMC8704492/ /pubmed/34940409 http://dx.doi.org/10.3390/membranes11120909 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kwon, Oh-Hoon
Cho, Yoon Young
Lee, Jung Hee
Chung, Sungkwon
O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains
title O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains
title_full O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains
title_fullStr O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains
title_full_unstemmed O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains
title_short O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains
title_sort o-glcnacylation inhibits endocytosis of amyloid precursor protein by decreasing its localization in lipid raft microdomains
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704492/
https://www.ncbi.nlm.nih.gov/pubmed/34940409
http://dx.doi.org/10.3390/membranes11120909
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