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

• Published in: Biomedicines Vol. 11; no. 6; p. 1685
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.06.2023; MDPI
• Subjects: Amino acids; Antibodies; Cancer therapies; Chemical compounds; Down-regulation; Drug development; drug screen; Drug screening; Drugs; EGFR pathway inhibitor; Epidermal growth factor receptors; Health aspects; Immunoglobulins; Immunoprecipitation; interaction; Kinases; Laboratories; Natural products; Nervous system diseases; Neurodegenerative diseases; osimertinib; Parkinson's disease; Physiology; Plasmids; Post-translation; Post-translational modification; Protein transport; Proteins; Scientific equipment and supplies industry; Synuclein; Therapeutic targets; Ubiquitin; UBL3; α-synuclein; United States; Japan; United States > US; EGFR pathway inhibitor; downregulate; UBL3; osimertinib; interaction; α-synucleinopathies; drug screen; α-synuclein
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11061685

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 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.