In plants, the ethylene response factor transcription factors (specifically, ERF VII TFs, which all have a Met-Cys N-terminal sequence) undergo degradation under aerobic conditions through a ubiquitin-dependent N-degron pathway. Following removal of the initiator methionine by methionine aminopeptidase, the plant cysteine oxidase (PCO) enzymes oxidize the N-terminal cysteine to cysteine sulphinic acid to promote degradation. Masson et al. found that plant and human cells utilize the same N-degron mechanism during hypoxia. They tested two thiol dioxygenases that are structurally similar to PCOs as potential human candidates. Overexpression of cysteamine (2-aminoethanethiol) dioxygenase (ADO) was sufficient to decrease the expression of a known human N-end rule (Cys) substrate, RGS4. Expression of human ADO in quadruple pco mutant plants was able to rescue the developmental and hypoxic gene-regulation defects, confirming the shared mechanism. Mass spectrometric analysis revealed ADO-mediated dioxygenation on the N-terminal cysteine of RGS4, which was blocked under hypoxic conditions. This modification promoted high turnover of RGS4 in an oxygen-dependent manner. Finally, Masson et al. identified that interleukin-32 also underwent dioxygenation by ADO, revealing a diversity of potential substrates regulated by this conserved hypoxic degradation mechanism.
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Miura, G. Breathing the same air. Nat Chem Biol 15, 847 (2019). https://doi.org/10.1038/s41589-019-0359-6