A New Take on Prion Protein Dynamics in Cellular Trafficking

Abstract

The mobility of cellular prion protein (PrP^C) in specific cell membrane domains and among distinct cell compartments dictates its molecular interactions and directs its cell function. PrP^C works in concert with several partners to organize signaling platforms implicated in various cellular processes. The scaffold property of PrP^C is able to gather a molecular repertoire to create heterogeneous membrane domains that favor endocytic events. Dynamic trafficking of PrP^C through multiple pathways, in a well-orchestrated mechanism of intra and extracellular vesicular transport, defines its functional plasticity, and also assists the conversion and spreading of its infectious isoform associated with neurodegenerative diseases. In this review, we highlight how PrP^C traffics across intra- and extracellular compartments and the consequences of this dynamic transport in governing cell functions and contributing to prion disease pathogenesis.

Keywords: PrP; PrPC; PrPSc; endocytosis; exosomes; prion; trafficking; vesicles.

Figure 1

Biogenesis, location and endocytic trafficking of PrP^C. PrP^C translocation to the ER may result in four different topological isoforms: ^secPrP, ^NtmPrP, ^CtmPrP and cyPrP (bottom right corner). ^secPrP is the most common isoform and is directed to the cell membrane after processing and maturation through the secretory pathway. PrP^C is preferentially located in lipid raft domains on the plasma membrane, where it can be internalized through clathrin-mediated (1) and clathrin-independent (2–3) endocytic pathways. (1) Clathrin-mediated endocytosis is the main route for PrP^C internalization, involving dynamin and the membrane receptors LRP and LRP1. (2) Caveolae-mediated endocytosis is a form of clathrin-independent endocytosis, where PrP^C interacts with dynamin and/or caveolin-1. (3) Another form of clathrin-independent internalization is Cu²⁺-mediated endocytosis of PrP^C, which occurs due to its ability to bind to copper ions through the N-terminal domain, with the assistance of LRP1. Different endocytic compartments are identified by their specific proteins of the Rab GTPase family. As a result, of those processes, PrP^C can be sorted into the early (Rab5/Rab4/Rab6) or late endosomes (Rab7), as well as intraluminal vesicles (ILVs) in multivesicular bodies (MVBs) (Rab7), being targeted for recycling endosomes (Rab11), exosome secretion or lysosomal/autophagosomal degradation. Additionally, the ESCRT machinery assists PrP^C sorting into ILVs.

Figure 2

Prion infection mechanisms and PrP^Sc processing through autophagy. PrP^Sc is capable of catalyzing the conversion of PrP^C into the infectious isoform PrP^Sc, and its spreading is highly dependent on PrP^C trafficking throughout different mechanisms, such as (a) prion infection through GPI-painting, in which PrP^Sc from an infected cell attaches to the lipid rafts of another cell; (b) prion infection through tunneling nanotubes, including transfer of endolysosomal vesicles in these structures; and (c) prion infection via exosomes, occurring in different cells types. It is postulated that PrP^c-PrP^Sc conversion starts on the cell membrane (d) and continues throughout the endocytic trafficking (e–g). Once PrP^Sc-containing exosomes fuse with the surface of other cell membrane (e), PrP^Sc can be directed to different endocytic vesicles. Multivesicular bodies (MVBs) can carry PrP^Sc to the autophagosomal/lysosomal degradation pathway (h), or to intraluminal vesicles (ILVs) to be secreted as exosomes (g). Under physiological conditions, mTOR is inhibited via AMPK phosphorylation, and PrP^Sc is sorted into the autophagosome (identified by markers p62 and LC3), being degraded after autophago-lysosomal fusion (forming the autolysosome) (inset: T bars represent pathway inhibition) (i). However, in prion-like diseases, mTOR inhibits the interaction between ULK1 and AMPK through phosphorylation of ULK1, leading to the impairment of autophagy and PrP^Sc clearance (bottom right corner).