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Article

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

by
Bin Chen
1,
Md. Mahmudul Hasan
1,
Hengsen Zhang
1,
Qing Zhai
1,
A. S. M. Waliullah
1,
Yashuang Ping
1,
Chi Zhang
1,
Soho Oyama
1,
Mst. Afsana Mimi
1,
Yuna Tomochika
1,
Yu Nagashima
2,
Tomohiko Nakamura
3,
Tomoaki Kahyo
1,4,
Kenji Ogawa
5,
Daita Kaneda
6,
Minoru Yoshida
7,8,9 and
Mitsutoshi Setou
1,4,10,*
1
Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu 431-3192, Shizuoka, Japan
2
Institute for Medical Photonics Research, Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Shizuoka, Japan
3
Department of Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu 431-3192, Shizuoka, Japan
4
International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu 431-3192, Shizuoka, Japan
5
Laboratory of Veterinary Epizootiology, Department of Veterinary Medicine, Nihon University, Kameino 1866, Fujisawa 252-0880, Kanagawa, Japan
6
Choju Medical Institute, Fukushimura Hospital, Yamanaka-19-14 Noyoricho, Toyohashi 441-8124, Aichi, Japan
7
Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
8
Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Tokyo 113-8657, Japan
9
RIKEN Center for Sustainable Resource Science, Wako 351-0198, Saitama, Japan
10
Department of Systems Molecular Anatomy, Institute for Medical Photonics Research, Preeminent Medical Photonics Education & Research Center, 1-20-1 Handayama, Higashi-Ku, Hamamatsu 431-3192, Shizuoka, Japan
*
Author to whom correspondence should be addressed.
Biomedicines 2023, 11(6), 1685; https://doi.org/10.3390/biomedicines11061685
Submission received: 30 April 2023 / Revised: 7 June 2023 / Accepted: 8 June 2023 / Published: 10 June 2023
(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)
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Abstract

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.
Keywords: UBL3; α-synuclein; interaction; drug screen; EGFR pathway inhibitor; osimertinib; downregulate; α-synucleinopathies UBL3; α-synuclein; interaction; drug screen; EGFR pathway inhibitor; osimertinib; downregulate; α-synucleinopathies
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MDPI and ACS Style

Chen, B.; Hasan, M.M.; Zhang, H.; Zhai, Q.; Waliullah, A.S.M.; Ping, Y.; Zhang, C.; Oyama, S.; Mimi, M.A.; Tomochika, Y.; et al. UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib. Biomedicines 2023, 11, 1685. https://doi.org/10.3390/biomedicines11061685

AMA Style

Chen B, Hasan MM, Zhang H, Zhai Q, Waliullah ASM, Ping Y, Zhang C, Oyama S, Mimi MA, Tomochika Y, et al. UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib. Biomedicines. 2023; 11(6):1685. https://doi.org/10.3390/biomedicines11061685

Chicago/Turabian Style

Chen, Bin, Md. Mahmudul Hasan, Hengsen Zhang, Qing Zhai, A. S. M. Waliullah, Yashuang Ping, Chi Zhang, Soho Oyama, Mst. Afsana Mimi, Yuna Tomochika, and et al. 2023. "UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib" Biomedicines 11, no. 6: 1685. https://doi.org/10.3390/biomedicines11061685

APA Style

Chen, B., Hasan, M. M., Zhang, H., Zhai, Q., Waliullah, A. S. M., Ping, Y., Zhang, C., Oyama, S., Mimi, M. A., Tomochika, Y., Nagashima, Y., Nakamura, T., Kahyo, T., Ogawa, K., Kaneda, D., Yoshida, M., & Setou, M. (2023). UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib. Biomedicines, 11(6), 1685. https://doi.org/10.3390/biomedicines11061685

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