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UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib

Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn)...

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Autores principales: Chen, Bin, Hasan, Md. Mahmudul, Zhang, Hengsen, Zhai, Qing, Waliullah, A. S. M., Ping, Yashuang, Zhang, Chi, Oyama, Soho, Mimi, Mst. Afsana, Tomochika, Yuna, Nagashima, Yu, Nakamura, Tomohiko, Kahyo, Tomoaki, Ogawa, Kenji, Kaneda, Daita, Yoshida, Minoru, Setou, Mitsutoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295865/
https://www.ncbi.nlm.nih.gov/pubmed/37371780
http://dx.doi.org/10.3390/biomedicines11061685
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author Chen, Bin
Hasan, Md. Mahmudul
Zhang, Hengsen
Zhai, Qing
Waliullah, A. S. M.
Ping, Yashuang
Zhang, Chi
Oyama, Soho
Mimi, Mst. Afsana
Tomochika, Yuna
Nagashima, Yu
Nakamura, Tomohiko
Kahyo, Tomoaki
Ogawa, Kenji
Kaneda, Daita
Yoshida, Minoru
Setou, Mitsutoshi
author_facet Chen, Bin
Hasan, Md. Mahmudul
Zhang, Hengsen
Zhai, Qing
Waliullah, A. S. M.
Ping, Yashuang
Zhang, Chi
Oyama, Soho
Mimi, Mst. Afsana
Tomochika, Yuna
Nagashima, Yu
Nakamura, Tomohiko
Kahyo, Tomoaki
Ogawa, Kenji
Kaneda, Daita
Yoshida, Minoru
Setou, Mitsutoshi
author_sort Chen, Bin
collection PubMed
description Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future.
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spelling pubmed-102958652023-06-28 UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib Chen, Bin Hasan, Md. Mahmudul Zhang, Hengsen Zhai, Qing Waliullah, A. S. M. Ping, Yashuang Zhang, Chi Oyama, Soho Mimi, Mst. Afsana Tomochika, Yuna Nagashima, Yu Nakamura, Tomohiko Kahyo, Tomoaki Ogawa, Kenji Kaneda, Daita Yoshida, Minoru Setou, Mitsutoshi Biomedicines Article Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future. MDPI 2023-06-10 /pmc/articles/PMC10295865/ /pubmed/37371780 http://dx.doi.org/10.3390/biomedicines11061685 Text en © 2023 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
Chen, Bin
Hasan, Md. Mahmudul
Zhang, Hengsen
Zhai, Qing
Waliullah, A. S. M.
Ping, Yashuang
Zhang, Chi
Oyama, Soho
Mimi, Mst. Afsana
Tomochika, Yuna
Nagashima, Yu
Nakamura, Tomohiko
Kahyo, Tomoaki
Ogawa, Kenji
Kaneda, Daita
Yoshida, Minoru
Setou, Mitsutoshi
UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib
title UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib
title_full UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib
title_fullStr UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib
title_full_unstemmed UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib
title_short UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib
title_sort ubl3 interacts with alpha-synuclein in cells and the interaction is downregulated by the egfr pathway inhibitor osimertinib
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10295865/
https://www.ncbi.nlm.nih.gov/pubmed/37371780
http://dx.doi.org/10.3390/biomedicines11061685
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