TMEM165 is a Golgi protein whose deficiency causes a Congenital Disorder of Glycosylation (CDG). We have demonstrated that Mn2+ supplementation could suppress the glycosylation defects observed in TMEM165-deficient cells and that TMEM165 was a Mn2+-sensitive protein. In the Golgi, the other transmembrane protein capable to regulate Mn2+/Ca2+ 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 Mn2+-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 MnCl2 exposure in HHD cells than in control cells. We linked, using ICP-MS and GPP130 as a Golgi Mn2+ sensor, this higher Mn2+-induced sensitivity to a cytosolic Mn accumulation in MnCl2 supplemented HHD fibroblasts. Altogether, these results link the function of SPCA1 to the stability of TMEM165 in a pathological context of Hailey-Hailey disease.

中文翻译：

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SPCA1控制着TMEM165在Hailey-Hailey病中的稳定性。

TMEM165是一种高尔基蛋白，其缺乏会导致先天性糖基化障碍（CDG）。我们已经证明，补充Mn2 +可以抑制在TMEM165缺陷细胞中观察到的糖基化缺陷，并且TMEM165是Mn2 +敏感蛋白。在高尔基体中，另一个能够调节Mn2 + / Ca2 +稳态的跨膜蛋白是SPCA1，由ATP2C1基因编码。一份ATP2C1基因的缺失会导致Hailey-Hailey病（HHD），这是人类的棘皮病性皮肤疾病。我们的最新结果表明SPCA1和TMEM165之间存在意外的功能链接。为了阐明部分SPCA1缺乏的情况下的这种联系，使用HHD成纤维细胞评估TMEM165的表达，亚细胞定位和Mn2 +诱导的降解。与对照成纤维细胞相比，HHD患者成纤维细胞中TMEM165的表达和定位没有观察到差异。然而，我们证明对于成纤维细胞和角质形成细胞，与对照细胞相比，HMEM细胞中TMEM165表达对MnCl2暴露更敏感。我们使用ICP-MS和GPP130作为高尔基Mn2 +传感器，将这种更高的Mn2 +诱导的敏感性与补充MnCl2的HHD成纤维细胞中的胞质Mn积累相关。总之，这些结果在海利-海利病的病理背景下将SPCA1的功能与TMEM165的稳定性联系在一起。使用ICP-MS和GPP130作为高尔基Mn2 +传感器，这种较高的Mn2 +诱导的对MnCl2补充的HHD成纤维细胞中胞质Mn积累的敏感性。总之，这些结果在海利-海利病的病理背景下将SPCA1的功能与TMEM165的稳定性联系在一起。使用ICP-MS和GPP130作为高尔基Mn2 +传感器，这种较高的Mn2 +诱导的对MnCl2补充的HHD成纤维细胞中胞质Mn积累的敏感性。总之，这些结果在海利-海利病的病理背景下将SPCA1的功能与TMEM165的稳定性联系在一起。