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.
References:
Han, L., Q. Qu, D. Aydin, O. Panova, M.J. Robertson, Y. Xu, R.O. Dror, G. Skiniotis, and L. Feng. (2022). Structure and mechanism of the SGLT family of glucose transporters. Nature 601: 274-279.
Kamitori, K., M. Shirota, and Y. Fujiwara. (2022). Structural Basis of the Selective Sugar Transport in Sodium-Glucose Cotransporters. J. Mol. Biol. 434: 167464.
Li, Y., W. Wang, and H.Y. Lim. (2023). Drosophila transmembrane protein 214 (dTMEM214) regulates midgut glucose uptake and systemic glucose homeostasis. Dev Biol 495: 92-103.
Martín, M.G., E. Turk, M.P. Lostao, C. Kerner, and E.M. Wright. (1996). Defects in Na⁺/glucose cotransporter (SGLT1) trafficking and function cause glucose-galactose malabsorption. Nat. Genet. 12: 216-220.
Examples:
TC#	Name	Organismal Type	Example
8.A.209.1.1	TMEM214 of 689 aas and 1 TMS at about residue 500. It regulates the electrogenic Na⁺-coupled sugar symporter that actively transports D-glucose or D-galactose at the plasma membrane, with a Na⁺ to sugar coupling ratio of 2:1 (see, for example, TC# 2.a.1.7.26) Transport activity by SGLT is driven by a transmembrane Na⁺ electrochemical gradient (the smf) set by the Na⁺/K⁺ pump (Kamitori et al. 2022, Han et al. 2022). It plays a primary role in the transport of dietary monosaccharides from enterocytes to the blood and is responsible for the absorption of D-glucose and D-galactose across the apical brush-border membrane of enterocytes, whereas basolateral exit is provided by GLUT2. Additionally, SGLT functions as a D-glucose sensor in enteroendocrine cells, triggering the secretion of the incretins GCG and GIP that control food intake and energy homeostasis (Martín et al. 1996).		SGLT or SLC5A1 of Homo sapiens

8.A.209.1.2	TMEM214 of 677 aas and possibly as many as 3 or 4 TMSs at residues ~280, 490 and one or two at the C-terminal end of the protein. The functions and description have been published (Li et al. 2023). See the 8.A.209 family description for a brief summary.		TMEM214 of Drosophila melanogaster