Department of Molecular & Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Department of Public Health Sciences, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Dev Cell. 2022 Mar 14;57(5):654-669.e9. doi: 10.1016/j.devcel.2022.02.010. Epub 2022 Mar 4.
The response to oxygen availability is a fundamental process concerning metabolism and survival/death in all mitochondria-containing eukaryotes. However, the known oxygen-sensing mechanism in mammalian cells depends on pVHL, which is only found among metazoans but not in other species. Here, we present an alternative oxygen-sensing pathway regulated by ATE1, an enzyme ubiquitously conserved in eukaryotes that influences protein degradation by posttranslational arginylation. We report that ATE1 centrally controls the hypoxic response and glycolysis in mammalian cells by preferentially arginylating HIF1α that is hydroxylated by PHD in the presence of oxygen. Furthermore, the degradation of arginylated HIF1α is independent of pVHL E3 ubiquitin ligase but dependent on the UBR family proteins. Bioinformatic analysis of human tumor data reveals that the ATE1/UBR and pVHL pathways jointly regulate oxygen sensing in a transcription-independent manner with different tissue specificities. Phylogenetic analysis suggests that eukaryotic ATE1 likely evolved during mitochondrial domestication, much earlier than pVHL.
对氧气可用性的反应是所有含有线粒体的真核生物中关于代谢和生存/死亡的基本过程。然而，哺乳动物细胞中已知的氧感应机制依赖于仅在后生动物中发现的 pVHL，而在其他物种中则不存在。在这里，我们提出了一种由 ATE1 调节的替代氧感应途径，ATE1 是一种在真核生物中普遍保守的酶，通过翻译后精氨酸化影响蛋白质降解。我们报告称，ATE1 通过优先精氨酸化 HIF1α，在存在氧气的情况下由 PHD 羟化，从而在哺乳动物细胞中集中控制低氧反应和糖酵解。此外，精氨酸化 HIF1α 的降解不依赖于 pVHL E3 泛素连接酶，但依赖于 UBR 家族蛋白。对人类肿瘤数据的生物信息学分析表明，ATE1/UBR 和 pVHL 途径以转录独立的方式共同调节氧感应，具有不同的组织特异性。系统发育分析表明，真核生物的 ATE1 可能在细胞器内共生发生之前的早期就进化而来，这比 pVHL 要早得多。
