Prions are self-propagating conformations of proteins that can cause heritable phenotypic traits. Most yeast prions contain glutamine (Q)/asparagine (N)-rich domains that facilitate the accumulation of the protein into amyloid-like aggregates. Efficient transmission of these infectious aggregates to daughter cells requires that chaperones, including Hsp104 and Sis1, continually sever the aggregates into smaller “seeds.” We previously identified 11 proteins with Q/N-rich domains that, when overproduced, facilitate the de novo aggregation of the Sup35 protein into the [PSI +] prion state. Here, we show that overexpression of many of the same 11 Q/N-rich proteins can also destabilize pre-existing [PSI+] or [URE3] prions. We explore in detail the events leading to the loss (curing) of [PSI+] by the overexpression of one of these proteins, the Q/N-rich domain of Pin4, which causes Sup35 aggregates to increase in size and decrease in transmissibility to daughter cells. We show that the Pin4 Q/N-rich domain sequesters Hsp104 and Sis1 chaperones away from the diffuse cytoplasmic pool. Thus, a mechanism by which heterologous Q/N-rich proteins impair prion propagation appears to be the loss of cytoplasmic Hsp104 and Sis1 available to sever [PSI+].
Vyšlo v časopise: Heterologous Gln/Asn-Rich Proteins Impede the Propagation of Yeast Prions by Altering Chaperone Availability. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003236 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003236
1. PrusinerSB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216 : 136–144.
2. WicknerRB (1994) [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264 : 566–569.
3. DerkatchIL, BradleyME, HongJY, LiebmanSW (2001) Prions affect the appearance of other prions: the story of [PIN+]. Cell 106 : 171–182.
4. SondheimerN, LindquistS (2000) Rnq1: an epigenetic modifier of protein function in yeast. Mol Cell 5 : 163–172.
5. WicknerRB, MasisonDC, EdskesHK (1995) [PSI+] and [URE3] as yeast prions. Yeast 11 : 1671–1685.
6. SuzukiG, ShimazuN, TanakaM (2012) A yeast prion, Mod5, promotes acquired drug resistance and cell survival under environmental stress. Science 336 : 355–359.
7. CrowET, LiL (2011) Newly identified prions in budding yeast, and their possible functions. Semin Cell Dev Biol 22 : 452–459.
8. DePaceAH, SantosoA, HillnerP, WeissmanJS (1998) A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion. Cell 93 : 1241–1252.
9. HalfmannR, AlbertiS, KrishnanR, LyleN, O'DonnellCW, et al. (2011) Opposing effects of glutamine and asparagine govern prion formation by intrinsically disordered proteins. Mol Cell 43 : 72–84.
10. RossED, ToombsJA (2010) The effects of amino acid composition on yeast prion formation and prion domain interactions. Prion 4 : 60–65.
11. GloverJR, KowalAS, SchirmerEC, PatinoMM, LiuJJ, et al. (1997) Self-seeded fibers formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae. Cell 89 : 811–819.
12. KingCY, TittmannP, GrossH, GebertR, AebiM, et al. (1997) Prion-inducing domain 2–114 of yeast Sup35 protein transforms in vitro into amyloid-like filaments. Proc Natl Acad Sci U S A 94 : 6618–6622.
13. SerioTR, AGC, ASK, GJS, JJM, et al. (2000) Nucleated Conformational Conversion and the Replication of Conformational Information by a Prion Determinant. Science 289 : 1317–1321.
14. CollinsSR, DouglassA, ValeRD, WeissmanJS (2004) Mechanism of Prion Propagation: Amyloid Growth Occurs by Monomer Addition. PLoS Biol 2: e321 doi:10.1371/journal.pbio.0020321.
15. InoueY (2009) Life cycle of yeast prions: propagation mediated by amyloid fibrils. Protein Pept Lett 16 : 271–276.
16. ChernoffYO, LindquistSL, OnoB, Inge-VechtomovSG, LiebmanSW (1995) Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [PSI+]. Science 268 : 880–884.
17. HaslbergerT, BukauB, MogkA (2010) Towards a unifying mechanism for ClpB/Hsp104-mediated protein disaggregation and prion propagation. Biochem Cell Biol 88 : 63–75.
18. CoxB, NessF, TuiteM (2003) Analysis of the generation and segregation of propagons: entities that propagate the [PSI+] prion in yeast. Genetics 165 : 23–33.
19. EaglestoneSS, RuddockLW, CoxBS, TuiteMF (2000) Guanidine hydrochloride blocks a critical step in the propagation of the prion-like determinant [PSI+] of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 97 : 240–244.
20. KryndushkinDS, AlexandrovIM, Ter-AvanesyanMD, KushnirovVV (2003) Yeast [PSI+] prion aggregates are formed by small Sup35 polymers fragmented by Hsp104. J Biol Chem 278 : 49636–49643.
21. Satpute-KrishnanP, LangsethSX, SerioTR (2007) Hsp104-dependent remodeling of prion complexes mediates protein-only inheritance. PLoS Biol 5: e24 doi:10.1371/journal.pbio.0050024.
22. ShorterJ, LindquistS (2004) Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304 : 1793–1797.
23. TessarzP, MogkA, BukauB (2008) Substrate threading through the central pore of the Hsp104 chaperone as a common mechanism for protein disaggregation and prion propagation. Mol Microbiol 68 : 87–97.
24. HelsenCW, GloverJR (2012) A new perspective on Hsp104-mediated propagation and curing of the yeast prion [PSI+]. Prion 6 : 234–239.
25. RomanovaNV, ChernoffYO (2009) Hsp104 and prion propagation. Protein Pept Lett 16 : 598–605.
26. HungGC, MasisonDC (2006) N-terminal domain of yeast Hsp104 chaperone is dispensable for thermotolerance and prion propagation but necessary for curing prions by Hsp104 overexpression. Genetics 173 : 611–620.
27. MoosaviB, WongwigkarnJ, TuiteMF (2010) Hsp70/Hsp90 co-chaperones are required for efficient Hsp104-mediated elimination of the yeast [PSI+] prion but not for prion propagation. Yeast 27 : 167–179.
28. HelsenCW, GloverJR (2012) Insight into molecular basis of curing of [PSI+] prion by overexpression of 104-kDa heat shock protein (Hsp104). J Biol Chem 287 : 542–556.
29. WinklerJ, TyedmersJ, BukauB, MogkA (2012) Hsp70 targets Hsp100 chaperones to substrates for protein disaggregation and prion fragmentation. J Cell Biol 198 : 387–404.
30. MasisonDC, KirklandPA, SharmaD (2009) Influence of Hsp70s and their regulators on yeast prion propagation. Prion 3 : 65–73.
31. PerrettS, JonesGW (2008) Insights into the mechanism of prion propagation. Curr Opin Struct Biol 18 : 52–59.
32. MathurV, HongJY, LiebmanSW (2009) Ssa1 overexpression and [PIN+] variants cure [PSI+] by dilution of aggregates. J Mol Biol 390 : 155–167.
33. SchwimmerC, MasisonDC (2002) Antagonistic interactions between yeast [PSI+] and [URE3] prions and curing of [URE3] by Hsp70 protein chaperone Ssa1p but not by Ssa2p. Mol Cell Biol 22 : 3590–3598.
34. AronR, HigurashiT, SahiC, CraigEA (2007) J-protein co-chaperone Sis1 required for generation of [RNQ+] seeds necessary for prion propagation. Embo J 26 : 3794–3803.
35. HigurashiT, HinesJK, SahiC, AronR, CraigEA (2008) Specificity of the J-protein Sis1 in the propagation of 3 yeast prions. Proc Natl Acad Sci U S A 105 : 16596–16601.
36. Sondheimer NLN, CraigEA, LindquistS (2001) The role of Sis1 in the maintenance of the [RNQ+] prion. EMBO J 20 : 2435–2442.
37. HinesJK, LiX, DuZ, HigurashiT, LiL, et al. (2011) [SWI], the prion formed by the chromatin remodeling factor Swi1, is highly sensitive to alterations in Hsp70 chaperone system activity. PLoS Genet 7: e1001309 doi:10.1371/journal.pgen.1001309.
38. BagriantsevSN, GrachevaEO, RichmondJE, LiebmanSW (2008) Variant-specific [PSI+] Infection Is Transmitted by Sup35 Polymers within [PSI+] Aggregates with Heterogeneous Protein Composition. Mol Biol Cell 19 : 2433–2443.
39. TiptonKA, VergesKJ, WeissmanJS (2008) In vivo monitoring of the prion replication cycle reveals a critical role for Sis1 in delivering substrates to Hsp104. Mol Cell 32 : 584–591.
40. WinklerJ, TyedmersJ, BukauB, MogkA (2012) Chaperone networks in protein disaggregation and prion propagation. J Struct Biol 179 : 152–160.
41. KryndushkinD, WicknerRB (2007) Nucleotide exchange factors for Hsp70s are required for [URE3] prion propagation in Saccharomyces cerevisiae. Mol Biol Cell 18 : 2149–2154.
42. MoriyamaH, EdskesHK, WicknerRB (2000) [URE3] prion propagation in Saccharomyces cerevisiae: requirement for chaperone Hsp104 and curing by overexpressed chaperone Ydj1p. Mol Cell Biol 20 : 8916–8922.
43. CoxBS (1965) [PSI+], a cytoplasmic suppressor of super-suppressor in yeast. Heredity 20 : 505–521.
44. DerkatchIL, ChernoffYO, KushnirovVV, Inge-VechtomovSG, LiebmanSW (1996) Genesis and variability of [PSI+] prion factors in Saccharomyces cerevisiae. Genetics 144 : 1375–1386.
45. LiebmanSW, DerkatchIL (1999) The yeast [PSI+] prion: making sense of nonsense. J Biol Chem 274 : 1181–1184.
46. KingCY (2001) Supporting the structural basis of prion strains: induction and identification of [PSI+] variants. J Mol Biol 307 : 1247–1260.
47. Kochneva-PervukhovaNV, ChechenovaMB, ValouevIA, KushnirovVV, SmirnovVN, et al. (2001) [PSI+] prion generation in yeast: characterization of the ‘strain’ difference. Yeast 18 : 489–497.
48. ZhouP, DerkatchIL, UptainSM, PatinoMM, LindquistS, et al. (1999) The yeast non-Mendelian factor [ETA+] is a variant of [PSI+], a prion-like form of release factor eRF3. Embo J 18 : 1182–1191.
49. TanakaM, ChienP, NaberN, CookeR, WeissmanJS (2004) Conformational variations in an infectious protein determine prion strain differences. Nature 428 : 323–328.
50. ChernoffYO, DerkachIL, Inge-VechtomovSG (1993) Multicopy SUP35 gene induces de-novo appearance of psi-like factors in the yeast Saccharomyces cerevisiae. Curr Genet 24 : 268–270.
51. DerkatchIL, BradleyME, ZhouP, ChernoffYO, LiebmanSW (1997) Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae. Genetics 147 : 507–519.
52. DerkatchIL, BradleyME, MasseSV, ZadorskySP, PolozkovGV, et al. (2000) Dependence and independence of [PSI+] and [PIN+]: a two-prion system in yeast? Embo J 19 : 1942–1952.
53. BradleyME, EdskesHK, HongJY, WicknerRB, LiebmanSW (2002) Interactions among prions and prion “strains” in yeast. Proc Natl Acad Sci U S A 99 (Suppl 4) 16392–16399.
54. DerkatchIL, UptainSM, OuteiroTF, KrishnanR, LindquistSL, et al. (2004) Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the [PSI+] prion in yeast and aggregation of Sup35 in vitro. Proc Natl Acad Sci U S A 101 : 12934–12939.
55. MeriinAB, ZhangX, HeX, NewnamGP, ChernoffYO, et al. (2002) Huntington toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1. J Cell Biol 157 : 997–1004.
56. OsherovichLZ, WeissmanJS (2001) Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI+] prion. Cell 106 : 183–194.
57. ChoeYJ, RyuY, KimHJ, SeokYJ (2009) Increased [PSI+] appearance by fusion of Rnq1 with the prion domain of Sup35 in Saccharomyces cerevisiae. Eukaryot Cell 8 : 968–976.
58. VitrenkoYA, GrachevaEO, RichmondJE, LiebmanSW (2007) Visualization of aggregation of the Rnq1 prion domain and cross-seeding interactions with Sup35NM. J Biol Chem 282 : 1779–1787.
59. BradleyME, LiebmanSW (2003) Destabilizing interactions among [PSI+] and [PIN+] yeast prion variants. Genetics 165 : 1675–1685.
60. EdskesHK, GrayVT, WicknerRB (1999) The [URE3] prion is an aggregated form of Ure2p that can be cured by overexpression of Ure2p fragments. Proc Natl Acad Sci U S A 96 : 1498–1503.
61. KurahashiH, IshiwataM, ShibataS, NakamuraY (2008) A regulatory role of the Rnq1 nonprion domain for prion propagation and polyglutamine aggregates. Mol Cell Biol 28 : 3313–3323.
62. KurahashiH, PackCG, ShibataS, OishiK, SakoY, et al. (2011) [PSI+] aggregate enlargement in rnq1 nonprion domain mutants, leading to a loss of prion in yeast. Genes Cells 16 : 576–589.
63. ErhartE, HollenbergCP (1983) The presence of a defective LEU2 gene on 2 mu DNA recombinant plasmids of Saccharomyces cerevisiae is responsible for curing and high copy number. J Bacteriol 156 : 625–635.
64. PatinoMM, LiuJJ, GloverJR, LindquistS (1996) Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273 : 622–626.
65. ZhouP, DerkatchIL, LiebmanSW (2001) The relationship between visible intracellular aggregates that appear after overexpression of Sup35 and the yeast prion-like elements [PSI+] and [PIN+]. Mol Microbiol 39 : 37–46.
66. HongJY, MathurV, LiebmanSW (2011) A new colour assay for [URE3] prion in a genetic background used to score for the [PSI+] prion. Yeast 28 : 555–560.
67. Satpute-KrishnanP, SerioTR (2005) Prion protein remodelling confers an immediate phenotypic switch. Nature 437 : 262–265.
68. VishveshwaraN, BradleyME, LiebmanSW (2009) Sequestration of essential proteins causes prion associated toxicity in yeast. Mol Microbiol 73 : 1101–1114.
69. DerdowskiA, SindiSS, KlaipsCL, DiSalvoS, SerioTR (2011) A size threshold limits prion transmission and establishes phenotypic diversity. Science 330 : 680–683.
70. Kawai-NomaS, PackCG, TsujiT, KinjoM, TaguchiH (2009) Single mother-daughter pair analysis to clarify the diffusion properties of yeast prion Sup35 in guanidine-HCl-treated [PSI+] cells. Genes Cells 14 : 1045–1054.
71. ByrneLJ, CoxBS, ColeDJ, RidoutMS, MorganBJ, et al. (2007) Cell division is essential for elimination of the yeast [PSI+] prion by guanidine hydrochloride. Proc Natl Acad Sci U S A 104 : 11688–11693.
72. ChernoffYO (2007) Stress and prions: lessons from the yeast model. FEBS Lett 581 : 3695–3701.
73. FanQ, ParkKW, DuZ, MoranoKA, LiL (2007) The role of Sse1 in the de novo formation and variant determination of the [PSI+] prion. Genetics 177 : 1583–1593.
74. SadlishH, RampeltH, ShorterJ, WegrzynRD, AndreassonC, et al. (2008) Hsp110 chaperones regulate prion formation and propagation in S. cerevisiae by two discrete activities. PLoS ONE 3: e1763 doi:10.1371/journal.pone.0001763.
75. DisalvoS, DerdowskiA, PezzaJA, SerioTR (2011) Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation. Nat Struct Mol Biol 18 : 486–492.
76. WegrzynRD, BapatK, NewnamGP, ZinkAD, ChernoffYO (2001) Mechanism of prion loss after Hsp104 inactivation in yeast. Mol Cell Biol 21 : 4656–4669.
77. HuhWK, FalvoJV, GerkeLC, CarrollAS, HowsonRW, et al. (2003) Global analysis of protein localization in budding yeast. Nature 425 : 686–691.
78. DouglasPM, SummersDW, RenHY, CyrDM (2009) Reciprocal efficiency of RNQ1 and polyglutamine detoxification in the cytosol and nucleus. Mol Biol Cell 20 : 4162–4173.
79. IshiwataM, KurahashiH, NakamuraY (2009) A G-protein gamma subunit mimic is a general antagonist of prion propagation in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 106 : 791–796.
80. KryndushkinDS, EngelA, EdskesHK, WicknerRB (2011) Molecular Chaperone Hsp104 Can Promote Yeast Prion Generation. Genetics 188 : 339–348.
81. EdskesHK, WicknerRB (2002) Conservation of a portion of the S. cerevisiae Ure2p prion domain that interacts with the full-length protein. Proc Natl Acad Sci U S A 99 (Suppl 4) 16384–16391.
82. RipaudL, MailletL, CullinC (2003) The mechanisms of [URE3] prion elimination demonstrate that large aggregates of Ure2p are dead-end products. Embo J 22 : 5251–5259.
83. InoueY, Kawai-NomaS, Koike-TakeshitaA, TaguchiH, YoshidaM (2011) Yeast prion protein New1 can break Sup35 amyloid fibrils into fragments in an ATP-dependent manner. Genes Cells 16 : 545–556.
84. HinesJK, HigurashiT, SrinivasanM, CraigEA (2011) Influence of prion variant and yeast strain variation on prion-molecular chaperone requirements. Prion 5 : 238–244.
85. TreuschS, LindquistS (2012) An intrinsically disordered yeast prion arrests the cell cycle by sequestering a spindle pole body component. J Cell Biol 197 : 369–379.
86. MeriinABZX, AlexandrovIM, SalnikovaAB, Ter-AvanesianMD, ChernoffYO, ShermanMY (2007) Endocytosis machinery is involved in aggregation of proteins with expanded polyglutamine domains. FASEB J 21 : 1915–1925.
87. DuennwaldML, LindquistS (2008) Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity. Genes Dev 22 : 3308–3319.
88. GongH, RomanovaNV, AllenKD, ChandramowlishwaranP, GokhaleK, et al. (2012) Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast. PLoS Genet 8: e1002634 doi:10.1371/journal.pgen.1002634.
89. Ter-AvanesyanMD, KushnirovVV, DagkesamanskayaAR, DidichenkoSA, ChernoffYO, et al. (1993) Deletion analysis of the SUP35 gene of the yeast Saccharomyces cerevisiae reveals two non-overlapping functional regions in the encoded protein. Mol Microbiol 7 : 683–692.
90. GoldringES, GrossmanLI, KrupnickD, CryerDR, MarmurJ (1970) The petite mutation in yeast. Loss of mitochondrial deoxyribonucleic acid during induction of petites with ethidium bromide. J Mol Biol 52 : 323–335.
91. TuiteMF, MundyCR, CoxBS (1981) Agents that cause a high frequency of genetic change from [PSI+] to [psi−] in Saccharomyces cerevisiae. Genetics 98 : 691–711.
92. Sherman F, Fink, G R & Hicks, J B. (1986) Methods in Yeast Genetics;Sherman F, Fink, G. R. & Hicks, J. B., editor. Plainview, New York: Cold Spring Harbor Lab.
93. NehlinJO, CarlbergM, RonneH (1989) Yeast galactose permease is related to yeast and mammalian glucose transporters. Gene 85 : 313–319.
94. DouglasPM, TreuschS, RenHY, HalfmannR, DuennwaldML, et al. (2008) Chaperone-dependent amyloid assembly protects cells from prion toxicity. Proc Natl Acad Sci U S A 105 : 7206–7211.
95. Lippincott-SchwartzJ, SnappE, KenworthyA (2001) Studying protein dynamics in living cells. Nat Rev Mol Cell Biol 2 : 444–456.
96. BagriantsevS, LiebmanSW (2004) Specificity of prion assembly in vivo. [PSI+] and [PIN+] form separate structures in yeast. J Biol Chem 279 : 51042–51048.
97. Chernoff YONG, KumarJ, AllenK, ZinkAD (1999) Evidence for a protein mutator in yeast: role of the Hsp70-related chaperone ssb in formation, stability, and toxicity of the [PSI+] prion. Mol Cell Biol 19 : 8103–8112.
98. BrachmannA, BaxaU, WicknerRB (2005) Prion generation in vitro: amyloid of Ure2p is infectious. Embo J 24 : 3082–3092.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
