Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol.
A rare conformation of the prion protein, PrPSc, is found only in mammals with transmissible prion diseases and represents either the infectious agent itself or a major component of it. The mechanism for initiating PrPSc formation is unknown. We report that PrP retrogradely transported out of the endoplasmic reticulum produced both amorphous aggregates and a PrPSc-like conformation in the cytosol. The distribution between these forms correlated with the rate of appearance in the cytosol. Once conversion to the PrPSc-like conformation occurred, it was sustained. Thus, PrP has an inherent capacity to promote its own conformational conversion in mammalian cells. These observations might explain the origin of PrPSc.
Ma
Jiyan
J
Howard Hughes Medical Institute (HHMI), University of Chicago, Chicago, IL 60637, USA.
Lindquist
Susan
S
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D019286:Endopeptidase K / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons; D009842:Oligopeptides / Q000494:pharmacology; D018620:PrPSc Proteins / Q000737:chemistry* / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport; D012995:Solubility; D014162:Transfection; D014407:Tumor Cells, Cultured
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D009842:Oligopeptides; D018620:PrPSc Proteins; D011328:Prions; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C067713:lactacystin; D019286:Endopeptidase K; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine; C078846:epoxomicin