Abstract：
Copper is a critical element for eukaryotic life involved in numerous cellular functions, including redox balance, but is toxic in excess. Therefore, tight regulation of copper acquisition and homeostasis is essential for cell physiology and survival. Here, we identify a different regulatory mechanism for cellular copper homeostasis that requires the presence of an endogenous retroviral envelope glycoprotein called Refrex1. We show that cells respond to elevated extracellular copper by increasing the expression of Refrex1, which regulates copper acquisition through interaction with the main copper transporter CTR1. Downmodulation of Refrex1 results in intracellular copper accumulation leading to reactive oxygen species (ROS) production and subsequent apoptosis, which is prevented by copper chelator treatment. Our results show that Refrex1 has been co-opted for its ability to regulate copper entry through CTR1 in order to limit copper excess, redox imbalance, and ensuing cell death, strongly suggesting that other endogenous retroviruses may have similar metabolic functions among vertebrates.
摘要：
铜是参与许多细胞功能的真核生物的关键元素，包括氧化还原平衡，但有毒过量。因此,严格调节铜的获取和稳态是细胞生理和生存的关键。这里,我们确定了细胞铜稳态的不同调节机制，该机制需要内源性逆转录病毒包膜糖蛋白Refrex1的存在。我们表明，细胞通过增加Refrex1的表达来响应细胞外铜的升高，Refrex1通过与主要铜转运蛋白CTR1的相互作用来调节铜的获取。Refrex1的下调导致细胞内铜积累，导致活性氧（ROS）产生和随后的细胞凋亡。这是防止铜螯合剂处理。我们的结果表明，Refrex1已被增选为其通过CTR1调节铜进入的能力，以限制铜过量，氧化还原不平衡，随之而来的细胞死亡，强烈暗示其他内源性逆转录病毒可能在脊椎动物中具有相似的代谢功能。
