Department of Medicine, Wilf Family Cardiovascular Research Institute, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, New York, USA.
Department of Medicine, Wilf Family Cardiovascular Research Institute, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York City, New York, USA; Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy.
J Biol Chem. 2024 Aug;300(8):107567. doi: 10.1016/j.jbc.2024.107567. Epub 2024 Jul 11.
The Golgi compartment performs a number of crucial roles in the cell. However, the exact molecular mechanisms underlying these actions are not fully defined. Pathogenic mutations in genes encoding Golgi proteins may serve as an important source for expanding our knowledge. For instance, mutations in the gene encoding Transmembrane protein 165 (TMEM165) were discovered as a cause of a new type of congenital disorder of glycosylation (CDG). Comprehensive studies of TMEM165 in different model systems, including mammals, yeast, and fish uncovered the new realm of Mn homeostasis regulation. TMEM165 was shown to act as a Ca/Mn:H antiporter in the medial- and trans-Golgi network, pumping the metal ions into the Golgi lumen and protons outside. Disruption of TMEM165 antiporter activity results in defects in N- and O-glycosylation of proteins and glycosylation of lipids. Impaired glycosylation of TMEM165-CDG arises from a lack of Mn within the Golgi. Nevertheless, Mn insufficiency in the Golgi is compensated by the activity of the ATPase SERCA2. TMEM165 turnover has also been found to be regulated by Mn cytosolic concentration. Besides causing CDG, recent investigations have demonstrated the functional involvement of TMEM165 in several other pathologies including cancer and mental health disorders. This systematic review summarizes the available information on TMEM165 molecular structure, cellular function, and its roles in health and disease.
高尔基器在细胞中发挥着许多关键作用。然而，这些作用的确切分子机制尚未完全定义。编码高尔基蛋白的基因中的致病突变可能是扩展我们知识的重要来源。例如，编码跨膜蛋白 165（TMEM165）的基因突变被发现是一种新型糖基化缺陷（CDG）的原因。对不同模型系统（包括哺乳动物、酵母和鱼类）中的 TMEM165 进行的综合研究揭示了 Mn 稳态调节的新领域。TMEM165 被证明在中-高尔基网络和反高尔基网络中作为 Ca/Mn：H 反向转运体发挥作用，将金属离子泵入高尔基体腔室并将质子泵出。TMEM165 反向转运体活性的破坏导致蛋白质的 N-和 O-糖基化以及脂质的糖基化缺陷。TMEM165-CDG 的糖基化缺陷是由于高尔基体中缺乏 Mn 引起的。然而，高尔基体中 Mn 的不足可以通过 ATPase SERCA2 的活性来补偿。TMEM165 的周转率也被发现受到细胞溶质 Mn 浓度的调节。除了引起 CDG 外，最近的研究还表明 TMEM165 在包括癌症和精神健康障碍在内的几种其他疾病中的功能参与。本系统综述总结了 TMEM165 分子结构、细胞功能及其在健康和疾病中的作用的现有信息。
