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. 2011 Mar 29;108(13):5337-41.
doi: 10.1073/pnas.1102762108. Epub 2011 Mar 14.

Suicidal [PSI+] is a lethal yeast prion

Ryan P McGlinchey  1 , Dmitry Kryndushkin, Reed B Wickner
Affiliations

Suicidal [PSI+] is a lethal yeast prion

Ryan P McGlinchey et al. Proc Natl Acad Sci U S A. .

Abstract

[PSI(+)] is a prion of the essential translation termination factor Sup35p. Although mammalian prion infections are uniformly fatal, commonly studied [PSI(+)] variants do not impair growth, leading to suggestions that [PSI(+)] may protect against stress conditions. We report here that over half of [PSI(+)] variants are sick or lethal. These "killer [PSI(+)]s" are compatible with cell growth only when also expressing minimal Sup35C, lacking the N-terminal prion domain. The severe detriment of killer [PSI(+)] results in rapid selection of nonkiller [PSI(+)] variants or loss of the prion. We also report variants of [URE3], a prion of the nitrogen regulation protein Ure2p, that grow much slower than ure2Δ cells. Our findings give a more realistic picture of the impact of the prion change than does focus on "mild" prion variants.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Screening of Ade+ colonies for killer [PSI+]. Isolated Ade+ colonies were restreaked three times on −Ade −Ura + 10 μg/mL doxycycline before being stamped on FOA. Circled colonies have killer [PSI+]. The fractions of isolates with mild, sick, and killer [PSI+] are shown below.
Fig. 2.
Fig. 2.
Killer [PSI+] strains are sick because of Sup35p deficiency. Cells carrying killer [PSI+], a nontoxic [PSI+], and a [psi−] control were streaked on ½YPD with (A) or without (B) doxycycline (10 μg/mL).
Fig. 3.
Fig. 3.
Toxicity and instability of [PSI+] isolates. (A) Sick and killer [PSI+] candidates were streaked on ½YPD and on FOA plates. After 2 d of growth on ½YPD, strains were restreaked on FOA plates. (B–D) Individual sick [PSI+] and nontoxic [PSI+] colonies were streaked on ½YPD from FOA. (Lower) Single colonies restreaked on ½YPD are indicated.
Fig. 4.
Fig. 4.
Multiple Sup35NM-GFP foci for killer [PSI+] and single foci for benign [PSI+]. (A) Newly induced 74-D694 [PSI+] colonies that could not grow on FOA plates (killer [PSI+]) were transformed with the pSupNM-GFP plasmid directly from −Ade −Ura + doxycycline plates. Transformants were selected only for the presence of pSupNM-GFP and were highly heterogeneous by color. White and sectoring transformants appeared as a result of the loss of the Sup35C plasmid, and their [PSI+] has become benign. Red transformants still carry the Sup35C-expressing plasmid and contained [PSI+] (probably killer [PSI+]), as was shown by fluorescent microscopy analysis. (B and C) Red transformants from A of two independent killer [PSI+] variants contain [PSI+] and show cells with multiple Sup35NM-GFP foci. (D) Typical white transformants from A and benign 74-D694 [PSI+] isolates show cells with mostly single Sup35NM-GFP foci. Six benign [PSI+] and four killer [PSI+] isolates were transformed as described in A. Transformants of both [PSI+] types that tend to retain the Sup35C plasmid were compared, and about 2,000 individual cells containing [PSI+] were analyzed for the presence of multiple Sup35NM-GFP foci per cell by fluorescent microscopy analysis. About 50% of putative killer [PSI+] cells had multiple foci, compared with only about 10% of benign [PSI+] cells under these conditions.
Fig. 5.
Fig. 5.
Spontaneously formed [URE3] clones with dramatically slowed growth and mitotic instability. BY241 (A), BY241 Δure2::TRP1 (B), BY241 individual spontaneously formed [URE3] colonies (C–F), and second streaks of small BY241 [URE3] colonies (G and H) from E and F. All strains were grown on ½YPD for 3 d before the pictures were taken.
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