Sun Shumin, Xie Enjun, Xu Shan, Ji Suyu, Wang Shufen, Shen Jie, Wang Rong, Shen Xinyi, Su Yunxing, Song Zijun, Wu Xiaotian, Zhou Jiahui, Cai Zhaoxian, Li Xiaopeng, Zhang Yan, Min Junxia, Wang Fudi
The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Zhejiang University School of Medicine, Hangzhou, 310058, China.
The Second Affiliated Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Adv Sci (Weinh). 2024 Dec;11(46):e2406421. doi: 10.1002/advs.202406421. Epub 2024 Oct 18.
The essential trace element, zinc, regulates virtually all aspects of cellular physiology, particularly cell proliferation and survival. Diverse families of metal transporters, metallothioneins, and metal-responsive transcriptional regulators are linked to zinc homeostasis. However, the mechanism underlying the regulation of systemic zinc homeostasis remains largely unknown. Here, it is reported that the intestinal transporter SLC30A1 plays an essential role in maintaining systemic zinc homeostasis. Using several lines of tissue-specific knockout mice, it is found that intestinal Slc30a1 plays a critical role in survival. Furthermore, lineage tracing reveals that Slc30a1 is localized to the basolateral membrane of intestinal epithelial cells (IECs). It is also found that Slc30a1 safeguards both intestinal barrier integrity and systemic zinc homeostasis. Finally, an integrative analysis of the cryo-EM structure and site-specific mutagenesis of human SLC30A1 are performed and a zinc transport mechanism of SLC30A1 unique within the SLC30A family, with His43 serving as a critical residue for zinc selectivity, is identified.
必需微量元素锌几乎调节细胞生理学的所有方面，尤其是细胞增殖和存活。不同的金属转运蛋白家族、金属硫蛋白和金属反应性转录调节因子都与锌稳态相关。然而，系统锌稳态调节的潜在机制在很大程度上仍然未知。在此，有报道称肠道转运蛋白SLC30A1在维持系统锌稳态中起重要作用。使用多种组织特异性敲除小鼠品系，发现肠道Slc30a1在生存中起关键作用。此外，谱系追踪显示Slc30a1定位于肠道上皮细胞（IEC）的基底外侧膜。还发现Slc30a1既能保护肠道屏障完整性，又能维持系统锌稳态。最后，对人SLC30A1的冷冻电镜结构和位点特异性诱变进行了综合分析，并确定了SLC30A1在SLC30A家族中独特的锌转运机制，其中His43是锌选择性的关键残基。
