Syntaxin 5 Is Required for Copper Homeostasis in <em>Drosophila</em> and Mammals

Copper is essential for aerobic life, but many aspects of its cellular uptake and distribution remain to be fully elucidated. A genome-wide screen for copper homeostasis genes in Drosophila melanogaster identified the SNARE gene Syntaxin 5 (Syx5) as playing an important role in copper regulation; flies heterozygous for a null mutation in Syx5 display increased tolerance to high dietary copper. The phenotype is shown here to be due to a decrease in copper accumulation, a mechanism also observed in both Drosophila and human cell lines. Studies in adult Drosophila tissue suggest that very low levels of Syx5 result in neuronal defects and lethality, and increased levels also generate neuronal defects. In contrast, mild suppression generates a phenotype typical of copper-deficiency in viable, fertile flies and is exacerbated by co-suppression of the copper uptake gene Ctr1A. Reduced copper uptake appears to be due to reduced levels at the plasma membrane of the copper uptake transporter, Ctr1. Thus Syx5 plays an essential role in copper homeostasis and is a candidate gene for copper-related disease in humans.铜对于有氧生命至关重要，但其细胞摄取与分布的诸多机制仍有待完全阐明。本研究通过对黑腹果蝇（Drosophila melanogaster）体内铜稳态相关基因开展全基因组筛选，鉴定出SNARE基因突触融合蛋白5（Syntaxin 5，Syx5）在铜调控过程中发挥关键作用；携带Syx5无效突变的杂合果蝇，对高膳食铜的耐受性显著提升。本研究证实该表型源于铜积累量降低，这一机制在果蝇与人类细胞系中均存在。对成年果蝇组织的研究显示，Syx5表达水平极低时会引发神经元功能缺陷并导致个体死亡，而表达水平过高同样会诱发神经元缺陷。与之相反，轻度敲降Syx5可在存活且可育的果蝇中引发典型的铜缺乏表型，且共敲降铜摄取基因Ctr1A会加剧该表型。铜摄取能力下降的原因，似乎是铜摄取转运蛋白Ctr1在质膜上的表达水平降低。综上，Syx5在铜稳态维持中发挥不可或缺的作用，可作为人类铜相关疾病的候选基因。