8.A.214. The TMEM214 Glucose Transporter Regulator (TMEM214) Family

TMEM214 is a critical mediator, in cooperation with CASP4, of ER-stress induced apoptosis. It is required for the activation of CASP4 following endoplasmic reticulum stress. It also regulates midgut glucose uptake and systemic glucose homeostasis in Drosophila melanogaster (Li et al. 2023). The sodium-glucose transporter 1 (SGLT1; SLC5A1), the primary glucose uptake transporter in the small intestine, is regulated by TMEM214. The Drosophila SLC5A1 exhibits properties consistent with a role in regulating the dietary sodium:glucose transporter in the Drosophila midgut, the equivalence of the mammalian small intestine.  Drosophila dTMEM214 acts in the midgut enterocytes to regulate systemic glucose homeostasis and glucose uptake. Li et al. 2023 showed that dTMEM214 resides in the apical membrane and cytoplasm of midgut enterocytes, and that the proper subcellular distribution of dTMEM214 in the enterocytes is regulated by the Rab4 GTPase. As a corollary, Rab4 loss-of-function phenocopies dTMEM214 loss-of-function in the midgut as shown by a decrease in enterocyte glucose uptake and an alteration in systemic glucose homeostasis. dTMEM214 regulates the apical membrane localization of dSLC5A1 in the enterocytes, thereby showing that dTMEM214 is a molecular regulator of glucose transporter in the midgut.