SPCA1 governs the stability of TMEM165 in Hailey-Hailey disease.

TMEM165 is a Golgi protein whose deficiency causes a Congenital Disorder of Glycosylation (CDG). We have demonstrated that Mn supplementation could suppress the glycosylation defects observed in TMEM165-deficient cells and that TMEM165 was a Mn-sensitive protein. In the Golgi, the other transmembrane protein capable to regulate Mn/Ca homeostasis is SPCA1, encoded by the ATP2C1 gene. A loss of one copy of the ATP2C1 gene leads to Hailey-Hailey Disease (HHD), an acantholytic skin disorder in Humans. Our latest results suggest an unexpected functional link between SPCA1 and TMEM165. In order to clarify this link in case of partial SPCA1 deficiency, HHD fibroblasts were used to assess TMEM165 expression, subcellular localization and Mn-induced degradation. No differences were observed regarding TMEM165 expression and localization in HHD patients' fibroblasts compared to control fibroblasts. Nevertheless, we demonstrated both for fibroblasts and keratinocytes that TMEM165 expression is more sensitive to MnCl exposure in HHD cells than in control cells. We linked, using ICP-MS and GPP130 as a Golgi Mn sensor, this higher Mn-induced sensitivity to a cytosolic Mn accumulation in MnCl supplemented HHD fibroblasts. Altogether, these results link the function of SPCA1 to the stability of TMEM165 in a pathological context of Hailey-Hailey disease.