Polyamines are essential organic polycations with multiple cellular functions relevant for cell division, cancer and ageing1,2,3. Regulation of polyamine synthesis is mainly achieved by controlling the activity of ornithine decarboxylase (ODC) through an unusual mechanism involving ODC antizyme1,4, the binding of which disrupts homodimeric ODC and targets it for ubiquitin-independent degradation by the 26S proteasome5. Whereas mammals express several antizyme genes6, we have identified a single orthologue, termed OAZ1, in Saccharomyces cerevisiae7. Similar to its mammalian counterparts, OAZ1 synthesis is induced with rising intracellular polyamine concentrations, which also inhibit ubiquitin-dependent degradation of the OAZ1 protein7. Together, these mechanisms contribute to a homeostatic feedback regulation of polyamines1,7,8. Antizyme synthesis involves a conserved +1 ribosomal frameshifting (RFS) event at an internal STOP codon during decoding of its messenger RNA6,7,8,9,10. Here we used S. cerevisiae OAZ1 to dissect the enigmatic mechanism underlying polyamine regulation of RFS. In contrast with previous assumptions, we report here that the nascent antizyme polypeptide is the relevant polyamine sensor that operates in cis to negatively regulate upstream RFS on the polysomes, where its own mRNA is being translated. At low polyamine levels, the emerging antizyme polypeptide inhibits completion of its synthesis causing a ribosome pile-up on antizyme mRNA, whereas polyamine binding to nascent antizyme promotes completion of its synthesis. Thus, our study reveals a novel autoregulatory mechanism, in which binding of a small metabolite to a nascent sensor protein stimulates the latter’s synthesis co-translationally.
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We thank M. Hochstrasser for comments, D. Richardson for critical reading of the manuscript, and D. H. Wolf for the pre1-1 strain. L.K. and D.G. were supported by the NRW Graduate School in Genetics and Functional Genomics. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Do 649/4) to R.J.D.
The authors declare no competing financial interests.
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Kurian, L., Palanimurugan, R., Gödderz, D. et al. Polyamine sensing by nascent ornithine decarboxylase antizyme stimulates decoding of its mRNA. Nature 477, 490–494 (2011). https://doi.org/10.1038/nature10393
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