Arginyltransferase1 mediates a pVHL‐independent oxygen sensing pathway in mammalian cells

The cellular response to oxygen availability is a fundamental process in all eukaryotes that regulates energy metabolism and death/survival decisions.The mechanisms for oxygen sensing likely co‐evolved with the domestication of mitochondria as an adaptation to the oxygenation of the earth atmosphere. However, in mammalian cells, the only known oxygen sensing mechanism depends on the Von Hippel–Lindau tumor suppressor protein (pVHL), which is only found in metazoans but not in other species. This discrepancy points to a potential missing link in oxygen sensing pathways. In this study, we found that oxygen sensing in mammalian cells is also regulated by Arginyltransferase 1 (ATE1), which is ubiquitously conserved in eukaryotes and influences the degradation of many proteins by posttranslational arginylation via the principle of N‐end rule. We report that ATE1 centrally controls the hypoxic response and glycolysis in mammalian cells by arginylating Hypoxia‐inducible factor 1a (HIF1a), and subsequently regulating HIF1a signaling pathways in a transcription‐independent manner. Moreover, we find that ATE1‐mediated N‐arginylation of HIF1a is sensitive to its oxygen‐dependent hydroxylation mediated by the oxygen sensor prolyl hydroxylase (PHD). However, ATE1 promotes HIF1a degradation independently of the conventional pVHL E3 ubiquitin ligase pathway, but depending on typical N‐end degradation machineries, the UBR E3 Ubiquitin ligase family. Bioinformatic analysis of human tumor data reveal that the ATE1/UBR and the pVHL pathway jointly regulate oxygen sensing in vivo with tissue specificities. Finally, a phylogenetic analysis suggests that ATE1 was derived from mitochondrial gene transfer and involved in oxygen‐sensing in multiple lineages of eukaryotes. Our findings present an unexplored role of ATE1‐mediated arginylation as a novel pathway for cellular oxygen sensing and adaptation in mammalian cells.