The evolutionarily conserved arginyltransferase 1 mediates a pVHL-independent oxygen-sensing pathway in mammalian cells.
The evolutionarily conserved arginyltransferase 1 mediates a pVHL-independent oxygen-sensing pathway in mammalian cells.
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DOI：
10.1016/j.devcel.2022.02.010
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发表时间：
2022-03-14
影响因子：
11.8
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Moorthy BT;Jiang C;Patel DM;Ban Y;O'Shea CR;Kumar A;Yuan T;Birnbaum MD;Gomes AV;Chen X;Fontanesi F;Lampidis TJ;Barrientos A;Zhang F
对氧可用性的反应是所有含线粒体真核生物代谢和生存/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pVHL， pVHL仅在后生动物中发现，而在其他物种中未发现。在这里，我们提出了由ATE1调节的另一种氧感应途径，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。我们报道，ATE1在哺乳动物细胞中通过优先将HIF1α精氨酸化来集中控制缺氧反应和糖酵解，而HIF1α在氧气存在下被PHD羟基化。此外，精氨酸化HIF1α的降解不依赖pVHL E3泛素连接酶，而依赖于UBR家族蛋白。人类肿瘤数据的生物信息学分析表明，ATE1/UBR和pVHL通路以转录不依赖的方式共同调节氧感知，具有不同的组织特异性。系统发育分析表明，真核ATE1可能在线粒体驯化过程中进化，比pVHL早得多。Moorthy等人发现了一种由ATE1而非pVHL介导的HIF1α氧依赖性降解的替代途径。与在后生动物外未发现的pVHL不同，ATE1在真核生物中是保守的，它的进化可能伴随着线粒体的驯化。
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. Moorthy et al. find an alternative pathway for oxygen-dependent degradation of HIF1α, mediated by ATE1 rather than pVHL. Unlike pVHL, which is not found outside metazoans, ATE1 is conserved throughout eukaryotes and its evolution likely accompanied the domestication of mitochondria.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
4.8
作者：
Davydov, IV;Varshavsky, A
通讯作者：
Varshavsky, A
影响因子：
14.9
作者：
Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
通讯作者：
Xavier RJ
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
DOI：
10.1073/pnas.96.22.12436
发表时间：
1999-10-26
影响因子：
11.1
作者：
Iwai, K;Yamanaka, K;Pause, A
通讯作者：
Pause, A