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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Synaptotagmins family affect glucose transport in retinal pigment epithelial cells through their ubiquitination-mediated degradation and glucose transporter-1 regulation
Hong Xu, Li-Bo Zhang, Yi-Yi Luo, Ling Wang, Ye-Pin Zhang, Pei-Qi Chen, Xue-Ying Ba, Jian Han, Heng Luo
Hong Xu, Li-Bo Zhang, Heng Luo, Department of Ophthalmology, The People’s Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China
Yi-Yi Luo, Xue-Ying Ba, Jian Han, Heng Luo, Precision Medicine Center of Chuxiong Yi Autonomous Prefecture, The People’s Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China
Ling Wang, Pei-Qi Chen, Department of Endocrinology, The People’s Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China
Ye-Pin Zhang, Department of Pathology, The People’s Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China
Author contributions: Xu H, Wang L, and Zhang LB performed the majority of the experiments and data analysis; Luo YY and Zhang YP performed some of the experiments and interpreted the results; Ba XY and Han J helped with sample preparation; Xu H and Zhang LB contributed to designing the project; Xu H and Zhang LB wrote the manuscript; Luo H revised the manuscript and designed and conducted the project; and all of the authors have read and approved the final manuscript.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of The People’s Hospital of Chuxiong Yi Autonomous Prefecture (Approval No. 2022-08).
Institutional animal care and use committee statement: All procedures involving animals were approved by the Animal Care and Use Committee of the People’s Hospital of Chuxiong Yi Autonomous Prefecture (Approval No. 2022-08).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Heng Luo, BMed, Bachelor, Department of Ophthalmology, The People’s Hospital of Chuxiong Yi Autonomous Prefecture & The Fourth Affiliated Hospital of Dali University, No. 318 Lucheng South Road, Chuxiong Yi Autonomous Prefecture 675000, Yunnan Province, China. lh18987837533@163.com
Received: October 19, 2023
Peer-review started: October 19, 2023
First decision: January 12, 2024
Revised: January 22, 2024
Accepted: March 11, 2024
Article in press: March 11, 2024
Published online: May 15, 2024
Processing time: 204 Days and 2 Hours
ARTICLE HIGHLIGHTS
Research background
Synaptotagmins (SYTs) are a family of 17 membrane transporters that function as calcium ion sensors during the release of Ca2+-dependent neurotransmitters and hormones. However, few studies have investigated whether members of the SYT family play a role in glucose uptake in diabetic retinopathy (DR) through Ca2+/glucose transporter-1 (GLUT1) and the possible related mechanisms.
Research motivation
To elucidate the role of the SYT family in the regulation of glucose transport in retinal pigment epithelial cells and explore its potential as a therapeutic target for the clinical management of DR.
Research objectives
To elucidate the role of SYT4 in the regulation of glucose transport in retinal pigment epithelial cells.
Research methods
DR was induced by streptozotocin in C57BL/6J mice in vivo and by high glucose medium in human retinal pigment epithelial cells (ARPE-19) in vitro. Bioinformatics analysis, reverse transcriptase-polymerase chain reaction, Western blot, flow cytometry, ELISA, HE staining and TUNEL staining were used for analysis.
Research results
Six proteins (SYT2, SYT3, SYT4, SYT7, SYT11, and SYT13) were found to be differentially expressed in DR, and SYT4 was highly expressed. Hyperglycemia induces the overexpression of SYT4, manipulates Ca2+ influx to induce the fusion of GLUT1 with the plasma membrane, promotes the abnormal expression of the glucose transporter GLUT1 and excessive cellular glucose uptake, induces ARPE-19 cell apoptosis, and promotes the progression of DR. Parkin deficiency inhibits the proteasomal degradation of SYT4 in DR, resulting in SYT4 accumulation and promoting GLUT1 fusion to the plasma membrane, and this process is blocked by oe-Parkin treatment. Moreover, dysregulation of Myelin transcription factor 1 (Myt1)-induced transcription of SYT4 in DR further activated the SYT4-mediated stimulus-secretion coupling process, and this process was inhibited in the oe-MYT1-treated group.
Research conclusions
The hyperglycemia-mediated overexpression of SYT4 manipulates Ca2+ influx to induce the fusion of GLUT1 to the plasma membrane, promote abnormal glucose transporter expression and cellular glucose uptake, and enhance the inflammatory response in cells, which in turn promotes DR progression. A lack of Parkin inhibited the proteasome-mediated degradation of SYT4 and promoted the fusion of GLUT1 with the plasma membrane, which upregulated the expression of GLUT1. Furthermore, the regulatory mechanism of the abnormally high expression of SYT4 was related to the dysregulation of the transcription factor Myt1.
Research perspectives
Our study reveals the key role of SYT4 in regulating glucose transport in retinal pigment epithelial cells during the pathogenesis of DR and the underlying mechanism and suggests potential therapeutic targets for clinical DR.
