Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress
Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress
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DOI：
10.3390/ijms21062002
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发表时间：
2020-03-01
影响因子：
5.6
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
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作者：
Engelhart, Darcy C.;Azad, Priti;Nigam, Sanjay K.
SLC 22转运蛋白家族广泛表达，在进化上保守，并通过转运代谢物、信号分子和抗氧化剂等有机小分子在调节体内平衡方面发挥重要作用。对果蝇转运蛋白的分析为研究药物转运蛋白的内源性功能提供了一个简单而直接的平台。对黑腹果蝇（Drosophila melanogaster）推定的SLC 22直系同源物的进化分析表明，虽然25个SLC 22果蝇直系同源物中的许多不属于先前建立的SLC 22亚分支，但至少有4个成员与哺乳动物SLC 22成员（SLC 22 A16：CG 6356、SLC 22 A15：CG 7458、CG 7442和SLC 22 A18：CG 3168）直系同源。我们通过敲除其中的14个基因，对SLC 22转运蛋白在果蝇中的作用进行了功能评估。三个假定的SLC 22直系同源基因敲除-CG 3168，CG 6356，和CG 7442/SLC 22 A-没有经历羽化，并在蛹阶段是致命的，表明这些基因的发育重要性。此外，通过百草枯测试，敲除四个SLC 22成员增加了对氧化应激的抗性（CG 4630：p <0.05，CG 6006：p < 0.05，CG 6126：p < 0.01和CG 16727：p < 0.05）。与最近的证据表明SLC 22是参与信号传导和代谢的遥感和信号网络（RSSN）的核心一致，这些表型支持SLC 22在处理活性氧方面的关键作用。
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 Drosophila melanogaster 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 Drosophila melanogaster by knocking down 14 of these genes. Three putative SLC22 ortholog knockdowns-CG3168, CG6356, and CG7442/SLC22A-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 (CG4630: p < 0.05, CG6006: p < 0.05, CG6126: p < 0.01 and CG16727: p < 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.