Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants.
journal contributionposted on 09.01.2020 by Norma Masson, Thomas P Keeley, Beatrice Giuntoli, Mark D White, Mikel Lavilla Puerta, Pierdomenico Perata, Richard J Hopkinson, Emily Flashman, Francesco Licausi, Peter J Ratcliffe
Any type of content formally published in an academic journal, usually following a peer-review process.
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-KmO2) 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.