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Contributed by Reed B. Wickner, September 9, 2020 (sent for review August 11, 2020; reviewed by Chih-Yen King and Susan Liebman)
Significance
[PSI+] is a prion (infectious protein) form of the yeast Sup35 protein, propagating as an amyloid filamentous polymer. We find that each of the ribosome-associated chaperones—Ssb1/2p, Zuo1p, and Ssz1p—at their normal expression levels, blocks [PSI+] generation and the propagation of most new [PSI+] prion variants generated in their absence. The curing mechanism involves the functional triad of ribosome-associated chaperones. Our results suggest that cells do not want to have a prion: Cells reduce the chance of a prion emerging at the polypeptide level, and usually immediately cure those prions that do arise perhaps by limiting fiber growth.
Abstract
The yeast prion [PSI+] is a self-propagating amyloid of the translation termination factor, Sup35p. For known pathogenic prions, such as [PSI+], a single protein can form an array of different amyloid structures (prion variants) each stably inherited and with differing biological properties. The ribosome-associated chaperones, Ssb1/2p (Hsp70s), and RAC (Zuo1p (Hsp40) and Ssz1p (Hsp70)), enhance de novo protein folding by protecting nascent polypeptide chains from misfolding and maintain translational fidelity by involvement in translation termination. Ssb1/2p and RAC chaperones were previously found to inhibit [PSI+] prion generation. We find that most [PSI+] variants arising in the absence of each chaperone were cured by restoring normal levels of that protein. [PSI+] variants hypersensitive to Ssb1/2p have distinguishable biological properties from those hypersensitive to Zuo1p or Ssz1p. The elevated [PSI+] generation frequency in each deletion strain is not due to an altered [PIN+], another prion that primes [PSI+] generation. [PSI+] prion generation/propagation may be inhibited by Ssb1/2/RAC chaperones by ensuring proper folding of nascent Sup35p, thus preventing its joining amyloid fibers. Alternatively, the effect of RAC/Ssb mutations on translation termination and the absence of an effect on the [URE3] prion suggest an effect on the mature Sup35p such that it does not readily join amyloid filaments. Ssz1p is degraded in zuo1Δ [psi-] cells, but not if the cells carry any of several [PSI+] variants. Our results imply that prions arise more frequently than had been thought but the cell has evolved exquisite antiprion systems that rapidly eliminate most variants.
Footnotes
- ↵1To whom correspondence may be addressed. Email: wickner{at}helix.nih.gov.
Author contributions: M.S. and R.B.W. designed research; M.S. performed research; M.S. contributed new reagents/analytic tools; M.S. and R.B.W. analyzed data; and M.S. and R.B.W. wrote the paper.
Reviewers: C-Y.K., Institute of Molecular Biology, Academia Sinica; and S.L., University of Nevada.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2016954117/-/DCSupplemental.
Data Availability.
All study data are included in the main text and SI Appendix.
Published under the PNAS license.
References
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Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants
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