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The prion hypothesis: from biological anomaly to basic regulatory mechanism

Nature Reviews Molecular Cell Biology volume 11, pages 823–833 (2010)Cite this article

Subjects

Key Points

  • An expanding group of proteins, known as prions, has been identified in fungi and mammals. Prions have the ability to confer unique phenotypes on cells and organisms by adopting self-replicating alternative conformations.

  • Although the mammalian prion protein (PrP) induces a fatal neurodegenerative disease following conformational conversion, changes in the structure of fungal prions are associated with the emergence of new phenotypes. These phenotypes represent gain-of-function and/or loss-of-function activities for the corresponding prion proteins.

  • In mammals, other proteins that show prion-like properties but lack infectivity (known as prionoids) can also gain new functions on conversion to a self-replicating conformation, suggesting that this process can also lead to a regulation of protein function in metazoans.

  • A multi-step pathway of conformational self-replication expands the range of phenotypes that each prion protein can specify and allows for dynamic transitions between forms.

  • The molecular basis of pathogenesis for the transmissible spongiform encephalopathies is not fully understood. Likewise, the relationship between the cause of disease and the normal function of the determinant PrP is an emerging concept. However, many aspects of prion biology can be explained by changes in the efficiency of conformational self-replication, suggesting that an unknown transient biochemical species mediates the biological effects of this alternative protein-folding pathway.

Abstract

Prions are unusual proteinaceous infectious agents that are typically associated with a class of fatal degenerative diseases of the mammalian brain. However, the discovery of fungal prions, which are not associated with disease, suggests that we must now consider the effect of these factors on basic cellular physiology in a different light. Fungal prions are epigenetic determinants that can alter a range of cellular processes, including metabolism and gene expression pathways, and these changes can lead to a range of prion-associated phenotypes. The mechanistic similarities between prion propagation in mammals and fungi suggest that prions are not a biological anomaly but instead could be a newly appreciated and perhaps ubiquitous regulatory mechanism.

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Figure 1: Cellular consequences of translational fidelity changes mediated by [PSI+].
Figure 2: Fungal prions and their associated phenotypes.
Figure 3: How prions are propagated in the cell.
Figure 4: Prion mixtures, strain competition and the species barrier.

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Acknowledgements

The research on yeast prions carried out in the Tuite laboratory is supported by funding from the UK Biotechnology and Biological Sciences Research Council and The Wellcome Trust, UK. Work in the Serio laboratory is supported by the US National Institutes of Health National Institute of General Medical Sciences (NIGMS) and the National Science Foundation (ADVANCE) USA. The authors thank members of the Tuite and Serio laboratories for critical reading of this manuscript before submission. The authors also thank S. Saupe, S. Liebman, C. Cullin and K. Stojanovski for providing images used in figure 2. The authors apologize that owing to space constraints they were unable to directly cite all primary studies that have contributed to our understanding of prion biology and its physiological effects.

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  1. Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, Kent, CT2 7NJ, UK

    Mick F. Tuite

  2. Department of Molecular Biology, Brown University, Cell Biology, and Biochemistry, Providence, 02912, Rhode Island, USA

    Tricia R. Serio

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Glossary

Epigenetic

A change in inherited phenotype resulting from a molecular event other than a change in the DNA sequence of the organism's genome: for example, DNA methylation or chromatin remodelling.

Protein conformation

The stable three-dimensional shape taken up by a polypeptide chain that determines the alternative functions of the protein.

Prion

A structurally altered form of a protein that can impose that form on a previously correctly folded form of the same protein and hence propagate the prion form by inheritance (yeast prions) or in an infectious manner (mammalian prion protein (PrP)).

Conformer

One of many different stable tertiary structures that can be taken up by a single polypeptide chain.

tRNA-mediated nonsense suppression

The translation of a termination codon by a tRNA with a mutation in its anticodon. This can result in partial restoration of function to the encoded protein when the codon is located within the open reading frame (a nonsense mutation).

+1/−1 ribosomal frameshifting

A net shift in the translation of an open reading frame by one base, either in the 3′ direction (+1) or 5′ direction (−1), that is directed by a specific signal in the mRNA sequence.

Vegetative incompatibility

Death of a multinucleate heterokaryon arising from the fusion of two different strains of a fungus, thereby preventing the transfer of cytoplasmic components from one strain to another.

Heterokaryon

Co-existence of two or more genetically different nuclei in a common cytoplasm.

De novo prion formation

The establishment of the prion form of a protein without the benefit of acquired prion seeds (propagons) or mutation; that is, spontaneous appearance of the prion form.

Prionoid

A protein that shows prion-like conformational self-replication activity but that lacks infectivity.

Melanosome

An organelle within melanocytes in which melanin is generated and stored.

Propagon

A conformation-replicating physical entity that is transmitted from mother to daughter cells and is required to maintain the [PRION+] phenotype. 'Seed' is a common synonym.

Strain 'mutation' or adaptation

The conversion of one prion conformer to another, either spontaneously or in response to a new environment.

Superinfection

Sequential but temporally spaced inoculations of a host with more than one strain of an infectious agent.

Overdominance

A heterozygous phenotype that is outside of the range of phenotypes for either homozygous state.

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Tuite, M., Serio, T. The prion hypothesis: from biological anomaly to basic regulatory mechanism. Nat Rev Mol Cell Biol 11, 823–833 (2010). https://doi.org/10.1038/nrm3007

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