Department of Biology, University of California San Diego, San Diego, CA 92093, USA.
Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA.
Int J Mol Sci. 2020 Mar 15;21(6):2002. doi: 10.3390/ijms21062002.
The SLC22 family of transporters is widely expressed, evolutionarily conserved, and plays a major role in regulating homeostasis by transporting small organic molecules such as metabolites, signaling molecules, and antioxidants. Analysis of transporters in fruit flies provides a simple yet orthologous platform to study the endogenous function of drug transporters in vivo. Evolutionary analysis of putative SLC22 orthologs reveals that, while many of the 25 SLC22 fruit fly orthologs do not fall within previously established SLC22 subclades, at least four members appear orthologous to mammalian SLC22 members (SLC22A16:CG6356, SLC22A15:CG7458, CG7442 and SLC22A18:CG3168). We functionally evaluated the role of SLC22 transporters in by knocking down 14 of these genes. Three putative SLC22 ortholog knockdowns-, , and -did not undergo eclosion and were lethal at the pupa stage, indicating the developmental importance of these genes. Additionally, knocking down four SLC22 members increased resistance to oxidative stress via paraquat testing ( < 0.05, < 0.05, < 0.01 and < 0.05). Consistent with recent evidence that SLC22 is central to a Remote Sensing and Signaling Network (RSSN) involved in signaling and metabolism, these phenotypes support a key role for SLC22 in handling reactive oxygen species.
SLC22 转运蛋白家族广泛表达，在进化上保守，通过转运代谢物、信号分子和抗氧化剂等小分子，在调节体内平衡方面发挥着重要作用。对果蝇转运蛋白的分析为研究体内药物转运蛋白的内源性功能提供了一个简单而同源的平台。对推定的 SLC22 直系同源物的进化分析表明，虽然 25 个果蝇 SLC22 直系同源物中的许多都不属于先前确定的 SLC22 亚科，但至少有四个成员与哺乳动物 SLC22 成员（SLC22A16：CG6356、SLC22A15：CG7458、CG7442 和 SLC22A18：CG3168）具有同源性。我们通过敲低这些基因中的 14 个，对 SLC22 转运蛋白在中的作用进行了功能评估。三个推定的 SLC22 直系同源物敲低物（、和）未能羽化，在蛹期致死，表明这些基因在发育中的重要性。此外，通过百草枯测试（<0.05、<0.05、<0.01 和<0.05）敲低四个 SLC22 成员可提高对氧化应激的抗性。最近的证据表明 SLC22 是涉及信号转导和代谢的远程感应和信号转导网络（RSSN）的核心，这些表型支持 SLC22 在处理活性氧方面的关键作用。
