Cellular phenotypes are a ‘readout’ of the complex interplay of genetic and epigenetic determinants that ultimately define a unique proteome and thereby specify cellular identity. However, modulation of the proteome itself is emerging as a key concept in our understanding of the molecular basis of phenotypic traits. Many studies over the past two decades have highlighted how regulated changes in protein modifications, such as phosphorylation and glycosylation, contribute to cellular phenotypes by altering protein abundance, function and localization. Such changes can in turn impact on complex regulatory pathways that control cellular phenotypes. But post-translational modifications are not the whole story; changes in protein conformation might also explain many phenotypic switches albeit by a mechanism that is not yet fully understood.
The prototypical and perhaps most extensively characterized example of protein conformation-based, inherited phenotypic traits are those defined by proteinaceous infectious particles known as prions
. These factors were originally identified as infectious entities associated with a group of transmissible neurodegenerative diseases in mammals1, 2
known as transmissible spongiform encephalopathies (TSEs) — such as Creudzfeldt–Jakob disease (CJD) and kuru in humans, scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle — the causative agent of which is resistant to treatments that damage nucleic acids.1, 3
The fact that prions could act as infectious agents despite the absence of a nucleic acid genome led to the formulation of the “protein-only” or prion hypothesis.1, 3
According to this idea, the TSE agent is a self-perpetuating conformer
of a host protein PrP (prion protein).1
The infectious conformer of this protein (PrPSc
) was predicted to recruit and convert the normal conformer PrPC
into the PrPSc
form through contacts between specific regions of the protein, thereby ‘replicating’ the agent during infection. A wealth of genetic and biochemical data now support this concept of conformational replication, leading to its near universal acceptance.
In addition to mammalian PrP, prions have also been found in two species of fungi, the yeast Saccharomyces cerevisiae
and the multicellular fungus Podospora anserina
This intriguing collection of functionally unrelated proteins can, like PrP, individually adopt a range of physical forms and transition between these states under physiological conditions. In all systems, these physical transitions specify new phenotypes, which may result from alterations to the normal function of the protein (gain-of-function and/or loss-of-function), the cellular response to the new protein conformation and/or the rate of accumulation of the altered form. Remarkably, these alternative conformers, each with a distinct yet stable three dimensional shape, are self-replicating and can be transferred between cells or organisms, allowing the associated traits to be transmitted as infectious diseases, as occurs in mammals5
, or inherited through cell division, as occurs in fungi.4
Although the mechanistic basis of prion propagation and transmission are emerging concepts in all systems, it is clear that these processes exist and ensure a level of genetic stability for prion-based epigenetic determinants that is in line with that of nucleic acid-based genetic determinants.
Box 1. Fungal prions, cytoplasmic inheritance and epigenetic regulation
In a genetic cross between haploid [PRION+
] and [prion−
] strains of Saccharomyces cerevisiae
, typically the resulting diploid is [PRION+
], and all meiotic progeny also carry the prion determinant.4
If the associated phenotype was controlled by a loss-of-function nuclear gene mutation then typically it would be recessive in a diploid, and a 2 [PRION+
]: 2 [prion−
] segregation pattern would be evident amongst the meiotic progeny. This non-Mendelian mode of inheritance shown by prions is indicative of transfer through the cytoplasm, which can also occur in other epigenetic systems, for example, mitochondrial petite
Inheritance of the [PRION+
] determinant generally results in the establishment of a new stable genetic state that can be maintained and propagated over many generations. In most cases inheritance of the [PRION+
] determinant will result in a change of phenotype when compared with the [prion−
] cell () that is not accompanied by a change in the nucleotide sequence of the prion protein-encoding gene, or for that matter, any other nuclear gene. Consequently, prions can rightly be viewed as epigenetic determinants that can affect cellular processes (see ). Prion-based epigenetic systems may have evolved because they can rapidly modify a cellular phenotype in response to a changing environment without introducing a change in the sequence and function of the genome.
In this Review we examine the expanding range of cellular processes and complex phenotypes that are determined by these epigenetic elements in fungi and in mammals and discuss how the process of conformational self-replication provides a framework for understanding the molecular basis of prion-associated phenotypes. As the number of identified prion proteins continues to grow, we suggest that the prion mechanism has now moved from the realm of a disease-causing biological anomaly to one of a novel regulator of cell phenotype.