The evolutionarily conserved arginyltransferase 1 mediates a pVHL-independent oxygen-sensing pathway in mammalian cells

Balaji T. Moorthy, Chunhua Jiang, Devang M. Patel, Yuguang Ban, Corin R. O'Shea, Akhilesh Kumar, Tan Yuan, Michael D. Birnbaum, Aldrin V. Gomes, Xi Chen, Flavia Fontanesi, Theodore J. Lampidis, Antoni Barrientos, Fangliang Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)654-669.e9
JournalDevelopmental Cell
Volume57
Issue number5
DOIs
StatePublished - Mar 14 2022
Externally publishedYes

Keywords

  • Arginylation
  • arginyltransferase
  • ATE1
  • degradation
  • glycolysis
  • HIF1α
  • hypoxic signaling
  • oxygen sensing
  • posttranslational protein modification
  • Warburg effect

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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