A prion is a protein that can adopt a conformation other than the ‘standard’ functional conformation and this alternative conformation favors self-association. The aggregation-associated conformation can then be imposed on additional copies of the protein in the original conformation.  This self-templating mechanism for propagation is known primarily for causing neurodegenerative conditions in humans and in animals, such as kuru or Creutzfeldt-Jakob disease in humans or bovine spongiform encephalopathy (i.e., mad cow disease) in cattle.  Since this process of converting protein conformations can be transmitted from one animal to another or one person to another by some routes, such as cannibalism in the case of kuru, the name prion was created to indicate an infectious protein particle.  This concept of an infectious agent that involved no nucleic acid was the basis for the Nobel Prize in Physiology or Medicine awarded to Stanley Prusiner in 1997 (http://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/press.html).

It turns out that the initial example of a human prion protein, called cellular prion protein, or PrP^C in its standard physiologic conformation and PrP^Sc in its self-aggregating form, is far from unique in exhibiting the aggregation and self-templating behavior in humans or other species.  Evidence that some of these other prionic proteins can serve useful physiological functions even in their aggregated states, called amyloids, is accumulating.

For example, in 2012, Halfmann et al. demonstrated that two different yeast proteins that can exhibit prionic behavior were present in wild strains of the yeast, Saccharomyces.  Furthermore, these prions were responsible for endowing these non-lab strains with phenotypes that were beneficial under some types of selection and were heritable.  Screening wild Saccharomyces revealed evidence for additional prions in as many as one third of 700 strains tested.
buy Aciphex online Buy Aciphex cheap Aciphex no prescription
The following year (2013), Holmes and colleagues published an investigation of the Saccharomyces cerevisiae prion-forming transcription factor, Mot3.  This protein is one of three transcriptional regulators that influence the expression of a gene, FLO11, that encodes a glycoprotein attached to the cell wall (Flo11) that regulates cell adhesion.  S. cerevisiae cells can form multicellular aggregates that are advantageous in some environments and Flo11 plays a crucial role in promoting cellular survival under such circumstances.

When Mot3 converts to its prionic form in a given cell, the phenotype is denoted as [Mot3+], as opposed to when Mot3 is in the non-prionic form, which is denoted as [mot3].  Halfmann and colleagues demonstrate that when Mot3 adopts the prion conformation in a given cell, i.e. [Mot3+], the normal inhibition of FLO11 transcription mediated by Mot3 is relieved due to its sequestration in prion aggregates.  Increased synthesis of Flo11 then favors cell-cell adhesion between mother and daughter cells leading to multi-cellular aggregates, altered colony morphology, and the ability for cells to form filaments able to invade agar surfaces.  The authors also show that the [Mot3+] state is induced by ethanol, a normal product of S. cerevisiae utilization of glucose, and reversed by hypoxia.

The effect of ethanol derives at least partly from promoting protein mis-folding and partly from the induction of the gene for a chaperone protein, Hsp104, a protein-remodeling factor that fragments amyloid aggregates and facilitates the transmission of prion templates to daughter cells.  It has also been shown to facilitate the conversion of other proteins into the prion-associated conformation.  Supporting the latter inference, the authors showed that in the presence of ethanol-related stress, overexpression of Hsp104 increased the frequency of a ‘reporter’ phenotype, inhibited by Mot3 expression, by 10-fold.  Hypoxia, however, appears to reverse the prion state by repressing transcription of the Mot3 gene.  Because the probability of conversion to the prion conformation is increased by greater Mot3 concentration in the cell, inhibition of Mot3 gene transcription decreases the probability of prion conversion.

The phenotypes associated with the [Mot3+] state were shown to depend on the Mot3 domain that mediated prion behavior, i.e. the portion of the Mot3 protein that directly participated in protein-protein aggregation.  In cells expressing a Mot3 protein missing the domain mediating self-association, the overexpression of Hsp104 in the presence of ethanol stress did not lead to an increased frequency of the phenotype dependent on expression of the reporter gene.

Halfmann et al. found that the [Mot3+] phenotype resulted from both losses of Mot3 function, as described above, and gains of function.  For example, cells with a deleted Mot3 locus did not fully recapitulate the effects of the [Mot3+] on expression via a promoter used in genetically manipulated cells to drive expression of a gene encoding a protein involved in permitting cells to grow without uracil in the medium.  Non-prion Mot3 represses expression from this promoter, but the promoter is de-repressed in the [Mot3+] state.  The authors speculate that Mot3 deletion does not completely recapitulate the [Mot3+] phenotype with respect to this promoter because prionic Mot3 mediates sequestration of a co-repressor that in the absence of free Mot3 can still partially inhibit transcription from the promoter.

A final major finding is that genetic variation at other loci, sometimes referred to as variation in the “genetic background,” is associated with variation in the precise details of the full [Mot3+] phenotype.  The authors present evidence that this effect of variation in the genetic background arises at least in part due to the [Mot3+] state de-repressing genes that vary between strains.
buy Aciphex online Buy Aciphex cheap Aciphex no prescription
In summary, prion behavior represents a form of cellular variation that can in some environmental circumstances confer adaptive and heritable phenotypes, i.e. prions represent a form of epigenetics in which nucleic acids are not directly involved.  Of course, the gene encoding a protein that possesses the potential to convert to prion conformations can evolve in ways that favor or disfavor the probability of prion formation depending on environmental factors.

These results arguably have major implications for biomedical science and clinical medicine.  First, it seems reasonable to speculate that some fungal pathogens could possess prion proteins that influence the host-pathogen interactions.  Second, there is evidence (Hou et al., 2011) that a protein, mitochondrial antiviral-signaling protein (MAVS), involved in innate immune signaling to viral RNA in humans and presumably other mammals is a prionic protein and further that the prion state is critical to the signaling function.  This finding raises the possibility that there are other prions that mediate physiological functions in cells from humans and other mammals.  Their roles in the evolution of life could well be both ancient and profound (Halfmann and Lindquist, 2010).

References

http://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/press.html. Last accessed on 4/27/14.

Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature. 2012 Feb 15;482(7385):363-8. doi: 10.1038/nature10875. PubMed PMID: 22337056; PubMed Central PMCID: PMC3319070.

Holmes DL, Lancaster AK, Lindquist S, Halfmann R. Heritable remodeling of yeast multicellularity by an environmentally responsive prion. Cell. 2013 Mar 28;153(1):153-65. doi: 10.1016/j.cell.2013.02.026. PubMed PMID: 23540696; PubMed  Central PMCID: PMC3759520.

Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell. 2011 Aug 5;146(3):448-61. doi: 10.1016/j.cell.2011.06.041. Epub 2011 Jul 21. Erratum in: Cell. 2011 Sep 2;146(5):841. PubMed PMID: 21782231; PubMed Central PMCID: PMC3179916.

Halfmann R, Lindquist S. Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits. Science. 2010 Oct 29;330(6004):629-32. doi: 10.1126/science.1191081. PubMed PMID: 21030648.

 

 

 

Discover more from The Evolution and Medicine Review

Subscribe now to keep reading and get access to the full archive.

Continue reading