Exploring the roles of TMEM165-SPCA1 in Golgi Mn2+ and Ca2+ homeostasis, Golgi glycosylation regulation and protein secretion, application to TMEM165-CDG and HHD diseases – ENIGMncA

The ionic homeostasis of organelles in the secretory pathway is crucial to many fundamental cellular processes such as vesicular fusion events, protein secretion as well as the activity of many glycosylation enzymes. This project aims to understand the interplay between TMEM165 (involved in a human pathology of glycosylation named CDG) and SPCA1 (involved in a human cutaneous pathology named Hailey-Hailey disease HHD) in the regulation of the Golgi Ca2+ and Mn2+homeostasis. Our preliminary results suggest that TMEM165 is a novel regulator of SPCA1's functions. The interaction between TMEM165-SPCA1 would tightly controls these two ionic homeostasis in order to adapt the glycosylation capacities to the speed of protein trafficking through the Golgi. A better knowledge of this pathway therefore appears fundamental for understanding the physiology and pathophysiology of TMEM165-CDG and HHD, as well as for the development of new therapies.