2. Academic Validation
  3. Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants

Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants

  • Science. 2019 Jul 5;365(6448):65-69. doi: 10.1126/science.aaw0112.
Norma Masson # 1,  Thomas P Keeley # 1,  Beatrice Giuntoli # 2 3,  Mark D White # 4,  Mikel Lavilla Puerta 3,  Pierdomenico Perata 3,  Richard J Hopkinson 4,  Emily Flashman # 4,  Francesco Licausi # 2 3,  Peter J Ratcliffe # 5 6
Affiliations

Affiliations

  • 1 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • 2 Department of Biology, University of Pisa, Via Luca Ghini 13, 56126 Pisa, Italy.
  • 3 Plantlab, Institute of Life Sciences, Scuola Superiore Sant'Anna, Via Guidiccioni 8/10, 56124 Pisa, Italy.
  • 4 Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
  • 5 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK. peter.ratcliffe@ndm.ox.ac.uk.
  • 6 The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • # Contributed equally.
PMID: 31273118 DOI: 10.1126/science.aaw0112
Abstract

Organisms must respond to hypoxia to preserve oxygen homeostasis. We identify a thiol oxidase, previously assigned as cysteamine (2-aminoethanethiol) dioxygenase (ADO), as a low oxygen affinity (high-K mO2) amino-terminal cysteine dioxygenase that transduces the oxygen-regulated stability of proteins by the N-degron pathway in human cells. ADO catalyzes the conversion of amino-terminal cysteine to cysteine sulfinic acid and is related to the plant cysteine oxidases that mediate responses to hypoxia by an identical posttranslational modification. We show in human cells that ADO regulates RGS4/5 (regulator of G protein signaling) N-degron substrates, modulates G protein-coupled calcium ion signals and mitogen-activated protein kinase activity, and that its activity extends to Other N-cysteine proteins including the angiogenic cytokine interleukin-32. Identification of a conserved enzymatic oxygen sensor in multicellular eukaryotes opens routes to better understanding and therapeutic targeting of adaptive responses to hypoxia.

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