title: Human prion protein binds Argonaute and promotes accumulation of microRNA effector complexes.
abstract: Despite intense research in the context of neurodegenerative diseases associated with its misfolding, the endogenous human prion protein PrP(C) (or PRNP) has poorly understood physiological functions. Whereas most PrP(C) is exposed to the extracellular environment, conserved domains result in transmembrane forms of PrP(C) that traffic in the endolysosomal system and are linked to inherited and infectious neuropathologies. One transmembrane PrP(C) variant orients the N-terminal 'octarepeat' domain into the cytoplasm. Here we demonstrate that the octarepeat domain of human PrP(C) contains GW/WG motifs that bind Argonaute (AGO) proteins, the essential components of microRNA (miRNA)-induced silencing complexes (miRISCs). Transmembrane PrP(C) preferentially binds AGO, and PrP(C) 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 PrP(C). We propose that dynamic interactions between PrP(C)-enriched endosomes and subcellular foci of AGO underpin these effects.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Biologie Moléculaire des Plantes, Strasbourg, France.
authors.forename: Derrick
authors.initials: D
authors.lastname: Gibbings
authors.forename: Pascal
authors.initials: P
authors.lastname: Leblanc
authors.forename: Florence
authors.initials: F
authors.lastname: Jay
authors.forename: Dominique
authors.initials: D
authors.lastname: Pontier
authors.forename: Fabrice
authors.initials: F
authors.lastname: Michel
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schwab
authors.forename: Sandrine
authors.initials: S
authors.lastname: Alais
authors.forename: Thierry
authors.initials: T
authors.lastname: Lagrange
authors.forename: Olivier
authors.initials: O
authors.lastname: Voinnet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060565:Argonaute Proteins / Q000032:analysis / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D018621:PrPC Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D060565:Argonaute Proteins; D001324:Autoantigens; D035683:MicroRNAs; D018621:PrPC Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C465663:TNRC6A protein, human; D043244:Ribonuclease III