Synaptotagmins family affect glucose transport in retinal pigment epithelial cells through their ubiquitination-mediated degradation and glucose transporter-1 regulation

Abstract

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 reported 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 regulatory mechanism of SYTs.

AIM

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.

METHODS

DR was induced by streptozotocin in C57BL/6J mice and by high glucose medium in human retinal pigment epithelial cells (ARPE-19). Bioinformatics analysis, reverse transcriptase-polymerase chain reaction, Western blot, flow cytometry, ELISA, HE staining, and TUNEL staining were used for analysis.

RESULTS

Six differentially expressed proteins (SYT2, SYT3, SYT4, SYT7, SYT11, and SYT13) were found between the DR and control groups, and SYT4 was highly expressed. Hyperglycemia induces SYT4 overexpression, manipulates Ca²⁺ influx to induce GLUT1 fusion with the plasma membrane, promotes abnormal expression of the glucose transporter GLUT1 and excessive glucose uptake, induces ARPE-19 cell apoptosis, and promotes DR progression. Parkin deficiency inhibits the proteasomal degradation of SYT4 in DR, resulting in SYT4 accumulation and enhanced GLUT1 fusion with the plasma membrane, and these effects were blocked by oe-Parkin treatment. Moreover, dysregulation of the 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.

CONCLUSION

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.

Keywords: Diabetic retinopathy; Glucose transporter-1; Synaptotagmin 4; Parkin; Myelin transcription factor 1

Core Tip: This study highlights the important role of synaptotagmin 4 (SYT4), which is a member of the SYTs family, in the regulation of glucose transport in retinal pigment epithelial cells during the development of diabetic retinopathy (DR). Hyperglycemia-induced overexpression of SYT4 perturbed calcium influx, resulting in the fusion of glucose transporter-1 (GLUT1) with the plasma membrane, abnormal expression of the glucose transporter GLUT1, and increased glucose uptake. Additionally, SYT4 contributed to apoptosis and inflammation, further exacerbating DR progression. This study also elucidated the molecular mechanisms by which Parkin and myelin transcription factor 1 modulate SYT4, providing new potential therapeutic targets for the clinical management of DR.