8.A.84 The Insulin Secretion Regulator TMEM59 (TMEM59) Family Glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells is regulated by several proteins including Tmem59l (Transmembrane protein 59 like), Scgn (Secretagogin), Gucy2c (Guanylate cyclase 2c), Slc29a4 (Solute carrier family 29, member 4), Cdhr1 (Cadherin-related family member 1) and Celsr2 (Cadherin EGF LAG seven-pass G-type receptor 2). These genes were knocked down in MIN6c4 cells, and the effects on insulin expression and secretion were analyzed. Suppression of Tmem59l, Scgn, and Gucy2c expression resulted in significantly decreased glucose- and/or KCl-stimulated insulin secretion, while the suppression of Slc29a4 expression resulted in increased insulin secretion. Tmem59l overexpression rescued the phenotype of the Tmem59l knockdown cells, and immunostaining analysis indicated that the TMEM59L protein colocalized with insulin and GM130, a Golgi complex marker. Thus, Tmem59l, Scgn, Gucy2c, and Slc29a4 may regulate GSIS.
References:
Chen, Y., R. Feng, G. Luo, J. Guo, Y. Wang, Y. Sun, L. Zheng, and T. Wen. (2018). DCF1 subcellular localization and its function in mitochondria. Biochimie 144: 50-55.
Gerlach, J.P., I. Jordens, D.V.F. Tauriello, I. van ''t Land-Kuper, J.M. Bugter, I. Noordstra, J. van der Kooij, T.Y. Low, F.X. Pimentel-Muiños, D. Xanthakis, N. Fenderico, C. Rabouille, A.J.R. Heck, D.A. Egan, and M.M. Maurice. (2018). TMEM59 potentiates Wnt signaling by promoting signalosome formation. Proc. Natl. Acad. Sci. USA 115: E3996-E4005.
Kobayashi, M., E. Yamato, K. Tanabe, F. Tashiro, S. Miyazaki, and J. Miyazaki. (2016). Functional Analysis of Novel Candidate Regulators of Insulin Secretion in the MIN6 Mouse Pancreatic β Cell Line. PLoS One 11: e0151927.
Mahfood, M., J. Chouchen, W. Kamal Eddine Ahmad Mohamed, A. Al Mutery, R. Harati, and A. Tlili. (2021). Whole exome sequencing, in silico and functional studies confirm the association of the mutation p.Cys169Tyr with deafness and suggest a role for the gene in the hearing process. Saudi J Biol Sci 28: 4421-4429.
Ullrich, S., A. Münch, S. Neumann, E. Kremmer, J. Tatzelt, and S.F. Lichtenthaler. (2010). The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein. J. Biol. Chem. 285: 20664-20674.
Examples:
TC#	Name	Organismal Type	Example
8.A.84.1.1	*TMEM59l of 342 aas and 2 TMSs, one N-terminal and one C-terminal. Plays a role in insulin secretion in β-cells of the pancreas (Kobayashi et al.* 2016).**		TMEM59l of Homo sapiens

8.A.84.1.2	Uncharacterized TMM59 protein of 289 aas and 2 TMSs, one N-terminal and one C-terminal TMSs.		*TMM59 protein of Strongylocentrotus purpuratus* (Purple sea urchin)**

8.A.84.1.3	Uncharacterized protein of 316 aas and 2 TMSs, N- and C-terminal.		UP of Rhipicephalus pulchellus

8.A.84.1.4	TMEM59, isoform 1 of 324 aas and 1 or 2 TMSs. TMEM59 or Dendritic cell factor 1 (DCF1) modulates both O- and N-glycosylation of proteins as well as cell surface expression and secretion of the amyloid precursor protein (Ullrich et al. 2010). It also potentiates Wnt signaling by promoting signalosome formation (Gerlach et al. 2018). Finally, it is localized to mitochondria, endosomes, lysosomes, endoplasmic reticulum, and proteasome. It regulates neural stem cell differentiation and dendritic spine formation (Chen et al. 2018). A role for the TMEM59 gene in the hearing process, and mutations in this gene give rise to deafness (Mahfood et al. 2021).		TMEM59 of Homo sapiens