Beyond the membrane: the overlooked nuclear localization of the prion protein

Although the prion protein (PrP) is best known as a glycosylphosphatidylinositol-anchored cell surface glycoprotein lacking canonical nucleic acid-binding domains, accumulating evidence indicates that it can be localized in the cytosol and nucleus and exhibits a remarkable ability to interact with both RNA and DNA molecules. A wide range of nucleic acids have been identified as PrP interactors, including cellular and viral RNAs, genomic and mitochondrial DNA, as well as highly structured nucleic acid motifs. For instance, G-quadruplexes and DNA hairpin aptamers, often display particularly high affinity for PrP. These observations suggest that PrP’s nucleic acid binding property is a potentially overlooked part of PrP biology, with possible implications for its physiological functions and pathological roles, including the formation of biomolecular condensates. While such condensates might participate in the spatiotemporal organization of PrP biological activities, their aging into less dynamic, gel- or solid-like assemblies could also contribute to pathological protein aggregation linked to prion disease pathogenesis. Herein, we review the literature about nuclear-associated PrP and discuss its molecular features relevant to nucleic-acid binding. Furthermore, we argue that PrP might harbor previously underappreciated nuclear functions as supported by microscopy and biochemical evidence reporting intranuclear and perinuclear PrP. We propose that this understudied nuclear localization of PrP might stem from the historical focus on membrane-associated PrP, and we call for renewed attention to its potential nuclear activities.