Human prion protein binds Argonaute and promotes accumulation of microRNA effector complexes

Despite intense research in the context of neurodegenerative diseases associated with its misfolding, the endogenous human prion protein PrPC (or PRNP) has poorly understood physiological functions. Whereas most PrPC is exposed to the extracellular environment, conserved domains result in transmembrane forms of PrPC that traffic in the endolysosomal system and are linked to inherited and infectious neuropathologies. One transmembrane PrPC variant orients the N-terminal 'octarepeat' domain into the cytoplasm. Here we demonstrate that the octarepeat domain of human PrPC contains GW/WG motifs that bind Argonaute (AGO) proteins, the essential components of microRNA (miRNA)-induced silencing complexes (miRISCs). Transmembrane PrPC preferentially binds AGO, and PrPC promotes formation or stability of miRISC effector complexes containing the trinucleotide repeat-containing gene 6 proteins (TNRC6) and miRNA-repressed mRNA. Accordingly, effective repression of several miRNA targets requires PrPC. We propose that dynamic interactions between PrPC-enriched endosomes and subcellular foci of AGO underpin these effects.