title: PrP-containing aggresomes are cytosolic components of an ER quality control mechanism.
abstract: Limited detoxification capacity often directs aggregation-prone, potentially hazardous, misfolded proteins to be deposited in designated cytosolic compartments known as 'aggresomes'. The roles of aggresomes as cellular quality control centers, and the cellular origin of the deposits contained within these structures, remain to be characterized. Here, we utilized the observation that the prion protein (PrP, also known as PRNP) accumulates in aggresomes following the inhibition of folding chaperones, members of the cyclophilin family, to address these questions. We found that misfolded PrP molecules must pass through the endoplasmic reticulum (ER) in order to be deposited in aggresomes, that the Golgi plays no role in this process and that cytosolic PrP species are not deposited in pre-existing aggresomes. Prior to their deposition in the aggresome, PrP molecules lose the ER localization signal and have to acquire a GPI anchor. Our discoveries indicate that PrP aggresomes are cytosolic overflow deposition centers for the ER quality control mechanisms and highlight the importance of these structures for the maintenance of protein homeostasis within the ER.
authors.affiliation: Biochemistry and Molecular Biology, the Institute for Medical Research Israel - Canada (IMRIC), the School of Medicine of the Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dubnikov
authors.affiliation: Biochemistry and Molecular Biology, the Institute for Medical Research Israel - Canada (IMRIC), the School of Medicine of the Hebrew University of Jerusalem, Jerusalem 91120, Israel Department of Obstetrics and Gynecology, Hadassah University Hospital, Ein Kerem, Jerusalem, 91120, Israel.
authors.forename: Tziona
authors.initials: T
authors.lastname: Ben-Gedalya
authors.affiliation: Biochemistry and Molecular Biology, the Institute for Medical Research Israel - Canada (IMRIC), the School of Medicine of the Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Robert
authors.initials: R
authors.lastname: Reiner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, Basel 4056, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, MD 20892, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, MD 20892, USA.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Biochemistry and Molecular Biology, the Institute for Medical Research Israel - Canada (IMRIC), the School of Medicine of the Hebrew University of Jerusalem, Jerusalem 91120, Israel ehudc@ekmd.huji.ac.il.
authors.forename: Ehud
authors.identifier: 0000-0001-5552-7086
authors.initials: E
authors.lastname: Cohen
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016572:Cyclosporine / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006031:Glycosylation; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D000072002:Prion Proteins / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects
chemical_list: D017261:Glycosylphosphatidylinositols; D000072002:Prion Proteins; D066329:Protein Aggregates; D016572:Cyclosporine
keywords: Aggresome; Endoplasmic reticulum; Neurodegeneration; Prion protein; Protein aggregation