Abstract
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.
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•ATE1 controls glycolysis and hypoxic response in mammalian cells by affecting HIF1α•HIF1α is arginylated by ATE1 and degraded by UBRs independently of pVHL•ATE1-dependent oxygen-sensing pathway evolved much earlier than the pVHL pathway
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.
