Abstract
Prions are infectious proteins that mostly replicate in self-propagating amyloid conformations (filamentous protein polymers) and consist of structurally altered normal soluble proteins. Prions can arise spontaneously in the cell without any clear reason and are generally considered fatal disease-causing agents that are only present in mammals. However, after the seminal discovery of two prions, [PSI+] and [URE3], in the eukaryotic model microorganism Saccharomyces cerevisiae, at least ten more prions have been discovered, and their biological and pathological effects on the host, molecular structure, and the relationship between prions and cellular components have been studied. In a filamentous fungus model, Podospora anserina, a vegetative incomparability-related [Het-s] prion that directly triggers cell death during anastomosis (hyphal fusion) was discovered. These prions in eukaryotic microbes have extended our understanding to overcome most fatal human prion/amyloid diseases. A prokaryotic microorganism (Clostridium botulinum) was reported to have a prion analog. The transcriptional regulators of C. botulinum-Rho can be converted into the self-replicating prion form ([RHO-X-C+]), which may affect global transcription. Here, we outline the major issues with prions in microbes and the lessons learned from the relatively uncovered microbial prion world.
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References
Alberti, S., Halfmann, R., King, O., Kapila, A., & Lindquist, S. (2009). A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell, 137, 146–158.
Alper, T., Haig, D. A., & Clarke, M. C. (1966). The exceptionally small size of the scrapie agent. Biochemical and Biophysical Research Communications, 22, 278–284.
Amor, A. J., Castanzo, D. T., Delany, S. P., Selechnik, D. M., van Ooy, A., & Cameron, D. M. (2015). The ribosome-associated complex antagonizes prion formation in yeast. Prion, 9, 144–164.
Bach, S., Talarek, N., Andrieu, T., Vierfond, J. M., Mettey, Y., Galons, H., Dormont, D., Meijer, L., Cullin, C., & Blondel, M. (2003). Isolation of drugs active against mammalian prions using a yeast-based screening assay. Nature Biotechnology, 21, 1075–1081.
Baxa, U., Wickner, R. B., Steven, A. C., Anderson, D., Marekov, L., Yau, W. M., & Tycko, R. (2007). Characterization of β-sheet structure in Ure2p1-89 yeast prion fibrils by solid state nuclear magnetic resonance. Biochemistry, 46, 13149–13162.
Bolton, D. C., McKinley, M. P., & Prusiner, S. B. (1982). Identification of a protein that purifies with the scrapie prion. Science, 218, 1309–1311.
Chakravarty, A. K., Smejkal, T., Itakura, A. K., Garcia, D. M., & Jarosz, D. F. (2020). A non-amyloid prion particle that activates a heritable gene expression program. Molecular Cell, 77, 251–265.
Chernoff, Y. O., & Kiktev, D. A. (2016). Dual role of ribosome-associated chaperones in prion formation and propagation. Current Genetics, 62, 677–685.
Chernoff, Y. O., & Ono, B. I. (1992). Dosage-dependent modifiers of Psi-dependent omnipotent suppression in yeast. In A. J. P. Brown, M. F. Tuite, & J. E. G. McCarthy (Eds.), Protein synthesis and targeting in yeast (pp. 101–107). Berlin: Springer.
Chernoff, Y. O., Lindquist, S. L., Ono, B. I., Inge-Vechtomov, S. G., & Liebman, S. W. (1995). Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science, 268, 880–884.
Chernoff, Y. O., Newnam, G. P., Kumar, J., Allen, K., & Zink, A. D. (1999). Evidence for a protein mutator in yeast: Role of the Hsp70-related chaperone ssb in formation, stability and toxicity of the [PSI+] prion. Molecular and Cellular Biology, 19, 8103–8112.
Chernova, T. A., Wilkinson, K. D., & Chernoff, Y. O. (2017). Prions, chaperones, and proteostasis in yeast. Cold Spring Harbor Perspectives in Biology, 9, a023663.
Collinge, J., Gorham, M., Hudson, F., Kennedy, A., Keogh, G., Pal, S., Rossor, M., Rudge, P., Siddique, D., Spyer, M., et al. (2009). Safety and efficacy of quinacrine in human prion disease (PRION-1 study): A patient-preference trial. The Lancet Neurology, 8, 334–344.
Coustou, V., Deleu, C., Saupe, S., & Begueret, J. (1997). The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proceedings of the National Academy of Sciences of the United States of America, 94, 9773–9778.
Cox, B. S. (1965). Ψ, a cytoplasmic suppressor of super-suppressor in yeast. Heredity, 20, 505–521.
D’Angelo, F., Vignaud, H., Di Martino, J., Salin, B., Devin, A., Cullin, C., & Marchal, C. (2013). A yeast model for amyloid-β aggregation exemplifies the role of membrane trafficking and PICALM in cytotoxicity. Disease Models & Mechanisms, 6, 206–216.
Dergalev, A. A., Alexandrov, A. I., Ivannikov, R. I., Ter-Avanesyan, M. D., & Kushnirov, V. V. (2019). Yeast Sup35 prion structure: Two types, four parts, many variants. International Journal of Molecular Sciences, 20, 2633.
Derkatch, I. L., Bradley, M. E., Hong, J. Y., & Liebman, S. W. (2001). Prions affect the appearance of other prions: the story of [PIN+]. Cell, 106, 171–182.
Diringer, H., Gelderblom, H., Hilmert, H., Özel, M., Edelbluth, C., & Kimberlin, R. H. (1983). Scrapie infectivity, fibrils and low molecular weight protein. Nature, 306, 476–478.
Du, Z., Park, K. W., Yu, H., Fan, Q., & Li, L. (2008). Newly identified prion linked to the chromatin-remodeling factor Swi1 in Saccharomyces cerevisiae. Nature Genetics, 40, 460–465.
Du, Z., Valtierra, S., Cardona, L. R., Dunne, S. F., Luan, C. H., & Li, L. (2019). Identifying anti-prion chemical compounds using a newly established yeast high-throughput screening system. Cell Chemical Biology, 26, 1664–1680.
Duennwald, M. L. (2013). Yeast as a platform to explore polyglutamine toxicity and aggregation. In D. Hatters & A. Hannan (Eds.), Tandem repeats in genes, proteins, and Disease: Methods and protocols (pp. 153–161). Totowa: Humana Press.
Edskes, H. K., Mukhamedova, M., Edskes, B. K., & Wickner, R. B. (2018). Hermes transposon mutagenesis shows [URE3] prion pathology prevented by a ubiquitin-targeting protein: Evidence for carbon/nitrogen assimilation cross-talk and a second function for Ure2p in Saccharomyces cerevisiae. Genetics, 209, 789–800.
Faria, C., Jorge, C. D., Borges, N., Tenreiro, S., Outeiro, T. F., & Santos, H. (2013). Inhibition of formation of α-synuclein inclusions by mannosylglycerate in a yeast model of Parkinson’s disease. Biochimica et biophysica acta, 1830, 4065–4072.
Fleming, E., Yuan, A. H., Heller, D. M., & Hochschild, A. (2019). A bacteria-based genetic assay detects prion formation. Proceedings of the National Academy of Sciences of the United States of America, 116, 4605–4610.
Gautschi, M., Lilie, H., Fünfschilling, U., Mun, A., Ross, S., Lithgow, T., Rücknagel, P., & Rospert, S. (2001). RAC, a stable ribosome-associated complex in yeast formed by the DnaK-DnaJ homologs Ssz1p and zuotin. Proceedings of the National Academy of Sciences of the United States of America, 98, 3762–3767.
Gautschi, M., Mun, A., Ross, S., & Rospert, S. (2002). A functional chaperone triad on the yeast ribosome. Proceedings of the National Academy of Sciences of the United States of America, 99, 4209–4214.
Gorkovskiy, A., Thurber, K. R., Tycko, R., & Wickner, R. B. (2014). Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid. Proceedings of the National Academy of Sciences of the United States of America, 111, E4615–E4622.
Gorkovskiy, A., Reidy, M., Masison, D. C., & Wickner, R. B. (2017). Hsp104 at normal levels cures many [PSI+] variants in a process promoted by Sti1p, Hsp90 and Sis1p. Proceedings of the National Academy of Sciences of the United States of America, 114, E4193–E4202.
Griffith, J. S. (1967). Nature of the scrapie agent: Self-replication and scrapie. Nature, 215, 1043–1044.
Groveman, B. R., Dolan, M. A., Taubner, L. M., Kraus, A., Wickner, R. B., & Caughey, B. (2014). Parallel in-register intermolecular β-sheet architectures for prion-seeded prion protein (PrP) amyloids. The Journal of Biological Chemistry, 289, 24129–24142.
Hung, G. C., & Masison, D. C. (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.
Itakura, A. K., Chakravarty, A. K., Jakobson, C. M., & Jarosz, D. F. (2020). Widespread prion-based control of growth and differentiation strategies in Saccharomyces cerevisiae. Molecular Cell, 77, 266–278.
Jaunmuktane, Z., & Brandner, S. (2020). Invited review: The role of prion-like mechanisms in neurodegenerative diseases. Neuropathology and Applied Neurobiology, 46, 522–545.
Jaunmuktane, Z., Mead, S., Ellis, M., Wadsworth, J. D., Nicoll, A. J., Kenny, J., Launchbury, F., Linehan, J., Richard-Loendt, A., Walker, A. S., et al. (2015). Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature, 525, 247–250.
Johnson, B. S., McCaffery, J. M., Lindquist, S., & Gitler, A. D. (2008). A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proceedings of the National Academy of Sciences of the United States of America, 105, 6439–6444.
Ju, S., Tardiff, D. F., Han, H., Divya, K., Zhong, Q., Maquat, L. E., Bosco, D. A., Hayward, L. J., Brown, R. H., Jr, Lindquist, S., et al. (2011). A yeast model of FUS/TLS-dependent cytotoxicity. PLoS Biology, 9, e1001052.
Kiktev, D. A., Melomed, M. M., Lu, C. D., Newnam, G. P., & Chernoff, Y. O. (2015). Feedback control of prion formation and propagation by the ribosome-associated chaperone complex. Molecular Microbiology, 96, 621–632.
Kim, S., Kwon, S. H., Kam, T. I., Panicker, N., Karuppagounder, S. S., Lee, S., Lee, J. H., Kim, W. R., Kook, M., Foss, C. A., et al. (2019). Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron, 103, 627–641.
Kirkland, P. A., Reidy, M., & Masison, D. C. (2011). Functions of yeast Hsp40 chaperone Sis1p dispensable for prion propagation but important for prion curing and protection from prion toxicity. Genetics, 188, 565–577.
Korth, C., May, B. C., Cohen, F. E., & Prusiner, S. B. (2001). Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proceedings of the National Academy of Sciences of the United States of America, 98, 9836–9841.
Kryndushkin, D., Shewmaker, F., & Wickner, R. B. (2008). Curing of the [URE3] prion by Btn2p, a Batten disease-related protein. The EMBO Journal, 27, 2725–2735.
Lacroute, F. (1971). Non-mendelian mutation allowing ureidosuccinic acid uptake in yeast. Journal of Bacteriology, 106, 519–522.
Levkovich, S. A., Rencus-Lazar, S., Gazit, E., & Bar-Yosef, L., D (2021). Microbial prions: Dawn of a new era. Trends in Biochemical Sciences, 46, 391–405.
Manogaran, A. L., Kirkland, K. T., & Liebman, S. W. (2006). An engineered nonsense URA3 allele provides a versatile system to detect the presence, absence and appearance of the [PSI+] prion in Saccharomyces cerevisiae. Yeast, 23, 141–147.
Masison, D. C., & Reidy, M. (2015). Yeast prions are useful for studying protein chaperones and protein quality control. Prion, 9, 174–183.
Masison, D. C., & Wickner, R. B. (1995). Prion-inducing domain of yeast Ure2p and protease resistance of Ure2p in prion-containing cells. Science, 270, 93–95.
Masters, C. L., Gajdusek, D. C., & Gibbs, C. J. (1981). Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Sträussler syndrome with an analysis of the various forms of amyloid plaque deposition in the virus-induced spongiform encephalopathies. Brain, 104, 559–588.
McKinley, M. P., Bolton, D. C., & Prusiner, S. B. (1983). A protease-resistant protein is a structural component of the scrapie prion. Cell, 35, 57–62.
Mukherjee, A., Morales-Scheihing, D., Salvadores, N., Moreno-Gonzales, I., Gonzales, C., Taylor-Presse, K., Mendez, N., Shahnawaz, M., Gaber, A. O., Sabek, O. M., et al. (2017). Inductionn of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism. The Journal of Experimental Medicine, 214, 2591–2610.
Nakayashiki, T., Ebihara, K., Bannai, H., & Nakamura, Y. (2001). Yeast [PSI+] “prions” that are crosstransmissible and susceptible beyond a species barrier through a quasi-prion state. Molecular Cell, 7, 1121–1130.
Nakayashiki, T., Kurtzman, C. P., Edskes, H. K., & Wickner, R. B. (2005). Yeast prions [URE3] and [PSI+] are diseases. Proceedings of the National Academy of Sciences of the United States of America, 102, 10575–10580.
Park, S. K., Park, S., Pentek, C., & Liebman, S. W. (2020). Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets. iScience, 24, 102000.
Parry, H. B. (1983). Scrapie disease in sheep: Historical, clinical, epidemiological, pathological and practical aspects of the natural disease. Academic Press.
Prusiner, S. B. (1982). Novel proteinaceous infectious particles cause scrapie. Science, 216, 136–144.
Prusiner, S. B., McKinley, M. P., Bowman, K. A., Bolton, D. C., Bendheim, P. E., Groth, D. F., & Glenner, G. G. (1983). Scrapie prions aggregate to form amyloid-like birefringent rods. Cell, 35, 349–358.
Roberts, B. T., & Wickner, R. B. (2003). A class of prions that propagate via covalent auto-activation. Genes & Development, 17, 2083–2087.
Sampson, T. R., Challis, C., Jain, N., Moiseyenko, A., Ladinsky, M. S., Shastri, G. G., Thron, T., Needham, B. D., Horvath, I., Debelius, J. W., et al. (2020). A gut bacterial amyloid promotes a-synuclein aggregation and motor impairment in mice. eLife, 9, e53111.
Saupe, S. J. (2000). Molecular genetics of heterokaryon incompatibility in filamentous ascomycetes. Microbiology and Molecular Biology Reviews, 64, 489–502.
Saupe, S. J. (2007). A short history of small s: A prion of the fungus Podospora anserina. Prion, 1, 110–115.
Saupe, S. J., & Daskalov, A. (2012). The [Het-s] prion, an amyloid fold as a cell death activation trigger. PLoS Pathogens, 8, e1002687.
Saupe, S., Descamps, C., Turcq, B., & Begueret, J. (1994). Inactivation of the Podospora anserina vegetative incompatibility locus het-c, whose product resembles a glycolipid transfer protein, drastically impairs ascospore production. Proceedings of the National Academy of Sciences of the United States of America, 91, 5927–5931.
Saupe, S. J., Jarosz, D. F., & True, H. L. (2016). Amyloid prions in fungi. Microbiology. Spectrum, 4, 10.
Shewmaker, F., Wickner, R. B., & Tycko, R. (2006). Amyloid of the prion domain of Sup35p has an in-register parallel β-sheet structure. Proceedings of the National Academy of Sciences of the United States of America, 103, 19754–19759.
Son, M., & Wickner, R. B. (2018). Nonsense-mediated mRNA decay factors cure most [PSI+] prion variants. Proceedings of the National Academy of Sciences of the United States of America, 115, E1184–E1193.
Son, M., & Wickner, R. B. (2020). Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants. Proceedings of the National Academy of Sciences of the United States of America, 117, 26298–26306.
Son, M., & Wickner, R. B. (2022a). Anti-prion systems in Saccharomyces cerevisiae turn an avalanche of prions into a flurry. Viruses, 14, 1945.
Son, M., & Wickner, R. B. (2022b). Antiprion systems in yeast cooperate to cure or prevent the generation of nearly all [PSI+] and [URE3] prions. Proceedings of the National Academy of Sciences of the United States of America, 119, e2205500119.
Steidle, E. A., Chong, L. S., Wu, M., Crooke, E., Fiedler, D., Resnick, A. C., & Rolfes, R. J. (2016). A novel inositol pyrophosphate phosphatase in Saccharomyces cerevisiae. The Journal of Biological Chemistry, 291, 6772–6783.
Suzuki, G., Shimazu, N., & Tanaka, M. (2012). A yeast prion, Mod5, promotes acquired drug resistance and cell survival under environmental stress. Science, 336, 355–359.
Tuite, M. F., Mundy, C. R., & Cox, B. S. (1981). Agents that cause a high frequency of genetic change from [psi+] to [psi] in Saccharomyces cerevisiae. Genetics, 98, 691–711.
Tycko, R. (2014). Physical and structural basis for polymorphism in amyloid fibrils. Protein Science, 23, 1528–1539.
Tycko, R., & Wickner, R. B. (2013). Molecular structures of amyloid and prion fibrils: Consensus vs. controversy. Accounts of Chemical Research, 46, 1487–1496.
Wang, J., Park, G., Lee, Y. K., Nguyen, M., San Fung, T., Lin, T. Y., Hsu, F., & Guo, Z. (2020). Spin label scanning reveals likely locations of β-strands in the amyloid fibrils of the Ure2 prion domain. ACS Omega, 5, 5984–5993.
Wickner, R. B. (1994). [URE3] as an altered URE2 protein: Evidence for a prion analog in Saccharomyces cerevisiae. Science, 264, 566–569.
Wickner, R. B., Dyda, F., & Tycko, R. (2008). Amyloid of Rnq1p, the basis of the [PIN+] prion, has a parallel in-register β-sheet structure. Proceedings of the National Academy of Sciences of the United States of America, 105, 2403–2408.
Wickner, R. B., Edskes, H. K., Bateman, D. A., Kelly, A. C., Gorkovskiy, A., Dayani, Y., & Zhou, A. (2013). Amyloids and yeast prion biology. Biochemistry, 52, 1514–1527.
Wickner, R. B., Beszonov, E., & Bateman, D. A. (2014). Normal levels of the antiprion proteins Btn2 and Cur1 cure most newly formed [URE3] prion variants. Proceedings of the National Academy of Sciences of the United States of America, 111, E2711–E2720.
Wickner, R. B., Shewmaker, F., Bateman, D. A., Edskes, H. E., Gorkovskiy, A., Dayani, Y., & Bezsonov, E. E. (2015). Yeast prions: Structure, biology and prion-handling systems. Microbiology and Molecular Biology Reviews, 79, 1–17.
Wickner, R. B., Kelly, A. C., Bezsonov, E. E., & Edskes, H. E. (2017). [PSI+] prion propagation is controlled by inositol polyphosphates. Proceedings of the National Academy of Sciences of the United States of America, 114, E8402–E8410.
Wickner, R. B., Bezsonov, E. E., Son, M., Ducatez, M., DeWilde, M., & Edskes, H. E. (2018). Anti-prion systems in yeast and inositol polyphosphates. Biochemistry, 57, 1285–1292.
Wickner, R. B., Son, M., & Edskes, B. K. (2019). Prion variants of yeast are numerous, mutable, and segregate on growth, affecting prion pathogenesis, transmission barriers and sensitivity to anti-prioin systems. Viruses, 11, 238.
Wickner, R. B., Edskes, H. K., Son, M., Wu, S., & Niznikiewicz, M. (2021). Innate immunity to prions: Anti-prion systems turn a tsunami of prions into a slow drip. Current Genetics, 67, 833–847.
Wong, S. H., & King, C. Y. (2015). Amino acid proximities in two Sup35 prion strains revealed by chemical cross-linking. The Journal of Biological Chemistry, 290, 25062–25071.
Yuan, A. H., & Hochschild, A. (2017). A bacterial global regulator forms a prion. Science, 355, 198–201.
Acknowledgements
This study was supported by the BK21 Four Program (Education/Research Group of Longevity and Marine Biotechnology for Innovative Talent) of Pusan National University (S.H. and S.L.), and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2022R1A2C1092397) (M.S.).
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Son, M., Han, S. & Lee, S. Prions in Microbes: The Least in the Most. J Microbiol. 61, 881–889 (2023). https://doi.org/10.1007/s12275-023-00070-4
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DOI: https://doi.org/10.1007/s12275-023-00070-4