title: Cyclosporin-A-induced prion protein aggresomes are dynamic quality-control cellular compartments.
abstract: Despite the activity of cellular quality-control mechanisms, subsets of mature and newly synthesized polypeptides fail to fold properly and form insoluble aggregates. In some cases, protein aggregation leads to the development of human neurodegenerative maladies, including Alzheimer's and prion diseases. Aggregates of misfolded prion protein (PrP), which appear in cells after exposure to the drug cyclosporin A (CsA), and disease-linked PrP mutants have been found to accumulate in juxtanuclear deposition sites termed 'aggresomes'. Recently, it was shown that cells can contain at least two types of deposition sites for misfolded proteins: a dynamic quality-control compartment, which was termed 'JUNQ', and a site for terminally aggregated proteins called 'IPOD'. Here, we show that CsA-induced PrP aggresomes are dynamic structures that form despite intact proteasome activity, recruit chaperones and dynamically exchange PrP molecules with the cytosol. These findings define the CsA-PrP aggresome as a JUNQ-like dynamic quality-control compartment that mediates the refolding or degradation of misfolded proteins. Together, our data suggest that the formation of PrP aggresomes protects cells from proteotoxic stress.
authors.affiliation: Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada (IMRIC), Hebrew University Medical School, Jerusalem 91120, Israel.
authors.forename: Tziona
authors.initials: T
authors.lastname: Ben-Gedalya
authors.forename: Roman
authors.initials: R
authors.lastname: Lyakhovetsky
authors.forename: Yifat
authors.initials: Y
authors.lastname: Yedidia
authors.forename: Michal
authors.initials: M
authors.lastname: Bejerano-Sagie
authors.forename: Natalya M
authors.initials: NM
authors.lastname: Kogan
authors.forename: Marcela Viviana
authors.initials: MV
authors.lastname: Karpuj
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaganovich
authors.forename: Ehud
authors.initials: E
authors.lastname: Cohen
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003459:Crystallins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D025801:Ubiquitin / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D003459:Crystallins; D018840:HSP70 Heat-Shock Proteins; D046912:Multiprotein Complexes; D011328:Prions; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; D016572:Cyclosporine; D046988:Proteasome Endopeptidase Complex