Transketolase regulates endoplasmic reticulum stress independent of its enzymatic activity in the retina

Transketolase is an enzyme in the pentose phosphate pathway, with nuclear localization and non-metabolic functions reported in various cancer and other cell types. This study explores the role of transketolase in the retina, with a focus on its involvement in endoplasmic reticulum (ER) stress. Using a VEGF-overexpressing mouse model of age-related macular degeneration (AMD), we examined transketolase expression and enzymatic activity. Our results show that while transketolase expression remains stable, its enzymatic activity is significantly reduced in the AMD retina. Chromatin immunoprecipitation sequencing revealed that transketolase regulates genes involved in cellular metabolism and ER protein processing, with pathways linked to neurodegenerative diseases. We also demonstrated that transketolase directly downregulates Ern1 expression. In human Müller cells, knockdown of transketolase resulted in increased ERN1 levels and aggravated ER stress. Interestingly, inhibiting transketolase’s enzymatic activity did not affect the ER stress response, while knockdown of transketolase did not affect the cellular metabolism. These findings suggest that knockdown of transketolase regulates Ern1 translation and ER stress in the retina, independent of its enzymatic function.