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The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion

Abstract

Although many proteins can misfold into a self-seeding amyloid-like conformation1, only six are known to be infectious, that is prions. The prions [PSI+], [PIN+], [URE3], [SWI+] and [HET-s] cause distinct heritable physiological changes in fungi2,3,4, whereas PrPSc causes infectious encephalopathies in mammals5. It is unknown whether 'protein-only' inheritance is limited to these exceptional cases or whether it represents a widespread mechanism of epigenetic control. Towards this goal, we now describe a new prion formed by the Cyc8 (Ssn6) protein of Saccharomyces cerevisiae. Analogously to other yeast prions, transient overproduction of a glutamine-rich region of Cyc8 induced a heritable dominant cyc8 phenotype that is transmitted cytoplasmically and is dependent on the chaperone Hsp104 and the continued presence of the Cyc8 protein. The evolutionarily conserved Cyc8–Tup1 global transcriptional repressor complex6 forms one of the largest gene regulatory circuits, controlling the expression of more than 7% of yeast genes7. Our finding that Cyc8 can propagate as a prion, together with a recent report that Swi1 of the Swi–Snf global transcriptional regulatory complex also has a prion form4, shows that prionization can lead to mass activation or repression of yeast genes and is suggestive of a link between the epigenetic phenomena of chromatin remodelling and prion formation.

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Figure 1: Overexpression of Cyc8's prion-like domain induces a cyc8 mutant phenotype.
Figure 2: [OCT+] phenotypes are dominant.
Figure 3: Inheritance of [OCT+] depends on Hsp104.
Figure 4: [OCT+] is a prion form of the Cyc8 protein.
Figure 5: [OCT+] cells show derepression of genes repressed by the Cyc8–Tup1 complex.

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Acknowledgements

We thank F. Sherman and R. Zitomer for yeast strains; R. Trumbly, H. Ronne, Y. Chernoff, S. Lindquist, M. Duennwald, M.D. Rose, S. Ruby, H. van Vuuren, I. Derkatch and M. Carlson for plasmids; and S.Y.R. Dent for anti-cyc8 and anti-Tup1 antibodies. We also thank K. Kirkland, V. Mathur, J. Hong and O. Appelebe for help with experiments; A. O'Dell for helpful suggestions; and S.-K. Park, A. Manogaran and N. Vishveshwara for commenting on the manuscript. This work was supported by NIH grant GM-56350 to S.W.L. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

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B.K.P. and J.G.S. performed experiments; S.W.L. conceived and coordinated the project; B.K.P. and S.W.L anlysed the data and wrote the manuscript.

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Correspondence to Susan W. Liebman.

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Patel, B., Gavin-Smyth, J. & Liebman, S. The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion. Nat Cell Biol 11, 344–349 (2009). https://doi.org/10.1038/ncb1843

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