More than Just a Phase: Prions at the Crossroads of Epigenetic Inheritance and Evolutionary Change

Abstract

A central tenet of molecular biology is that heritable information is stored in nucleic acids. However, this paradigm has been overturned by a group of proteins called "prions." Prion proteins, many of which are intrinsically disordered, can adopt multiple conformations, at least one of which has the capacity to self-template. This unusual folding landscape drives a form of extreme epigenetic inheritance that can be stable through both mitotic and meiotic cell divisions. Although the first prion discovered-mammalian PrP-is the causative agent of debilitating neuropathies, many additional prions have now been identified that are not obviously detrimental and can even be adaptive. Intrinsically disordered regions, which endow proteins with the bulk property of "phase-separation," can also be drivers of prion formation. Indeed, many protein domains that promote phase separation have been described as prion-like. In this review, we describe how prions lie at the crossroads of phase separation, epigenetic inheritance, and evolutionary adaptation.

Keywords: chaperones; prions; protein aggregation.

Figure 1.

Prions at the crossroads of three distinct ideas – intrinsically disordered proteins (IDPs), epigenetic inheritance and evolutionary adaptation in fluctuating environments. Intrinsically disordered regions in IDPs fuel the exploration of multiple conformational states. For prions, at least one such conformational state has the ability to self-template and is therefore heritable from one generation to the next. Epigenetic inheritance driven by prions produces different cell states in isogenic backgrounds. Such epigenetic states can be adaptive when faced with changing environments.

Figure 2.

Molecular and genetic hallmarks of prions. (left panel) The x-axis represents the conformational space explored by a prion protein. On this axis, the multimeric prion assembly and native conformer depict two distinct and stable structural states of the same prion polypeptide. On the y-axis, the functional states of these two distinct structural states are mapped. The functional difference in these two distinct and stable structural states manifests as separate naïve and [PRION⁺] traits, depicted in blue and green. The mechanism of prion formation and transmission to progeny fueling such epigenetic inheritance involves disaggregation by molecular chaperones to generate propagons that can be passed to the next generation. (right panel) Accessing two distinct phenotypic states (naïve in blue and [PRION⁺] in green) from the same polypeptide engenders distinctive behavior in genetic crosses. Prion-based traits are transmissible via cytoplasmic transfer, dominant in diploids, and passed to meiotic progeny in a non-Mendelian fashion. Most can also be permanently reverted to a naïve [prion^-] state from by transient chaperone inhibition. The unusual [PRION⁺] nomenclature for these protein-based genetic elements is derived from these behaviors.

Figure 3.

Prions are formed by a subset of intrinsically disordered proteins that have the ability to self-template. Many of these proteins interact with nucleic acids in their native states. Such prion-based epigenetic states are thus ideally poised to alter cellular information flow by affecting macromolecular transactions at each stage of the central dogma.