Cyclosporin-A-induced prion protein aggresomes are dynamic quality-control cellular compartments
Cyclosporin-A-induced prion protein aggresomes are dynamic quality-control cellular compartments
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.
Animals, CHO Cells, Cricetinae, Cricetulus, Crystallins/metabolism, Cyclosporine/pharmacology, HSP70 Heat-Shock Proteins/metabolism, Humans, Inclusion Bodies/metabolism, Multiprotein Complexes/metabolism, Prion Diseases/metabolism, Prions/genetics, Proteasome Endopeptidase Complex/metabolism, Protein Folding, Ubiquitin/metabolism, Ubiquitinated Proteins/metabolism
1891-1902
Ben-Gedalya, Tziona
10d368ec-f3bc-4aff-9a1d-6ddfc703a2b2
Lyakhovetsky, Roman
dd9f00c5-a583-4a79-a61a-b3088fa6e380
Yedidia, Yifat
16ad56f7-114e-4f7a-88f6-b96f70fbea93
Bejerano-Sagie, Michal
fcadf67a-7ce1-4e3b-9d75-9cb5725a9756
Kogan, Natalya M
9543396b-16cf-44f5-8a98-711e6dcbec8b
Karpuj, Marcela Viviana
d578e618-76bf-4e47-8800-51b161c2e182
Kaganovich, Daniel
ebb13f4e-e925-4aef-88e7-ddc25ef52d8f
Cohen, Ehud
831811ee-0aad-4863-bfda-55f1b012210e
1 June 2011
Ben-Gedalya, Tziona
10d368ec-f3bc-4aff-9a1d-6ddfc703a2b2
Lyakhovetsky, Roman
dd9f00c5-a583-4a79-a61a-b3088fa6e380
Yedidia, Yifat
16ad56f7-114e-4f7a-88f6-b96f70fbea93
Bejerano-Sagie, Michal
fcadf67a-7ce1-4e3b-9d75-9cb5725a9756
Kogan, Natalya M
9543396b-16cf-44f5-8a98-711e6dcbec8b
Karpuj, Marcela Viviana
d578e618-76bf-4e47-8800-51b161c2e182
Kaganovich, Daniel
ebb13f4e-e925-4aef-88e7-ddc25ef52d8f
Cohen, Ehud
831811ee-0aad-4863-bfda-55f1b012210e
Ben-Gedalya, Tziona, Lyakhovetsky, Roman, Yedidia, Yifat, Bejerano-Sagie, Michal, Kogan, Natalya M, Karpuj, Marcela Viviana, Kaganovich, Daniel and Cohen, Ehud
(2011)
Cyclosporin-A-induced prion protein aggresomes are dynamic quality-control cellular compartments.
Journal of Cell Science, 124 (11), .
(doi:10.1242/jcs.077693).
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.
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More information
Accepted/In Press date: 23 January 2011
Published date: 1 June 2011
Keywords:
Animals, CHO Cells, Cricetinae, Cricetulus, Crystallins/metabolism, Cyclosporine/pharmacology, HSP70 Heat-Shock Proteins/metabolism, Humans, Inclusion Bodies/metabolism, Multiprotein Complexes/metabolism, Prion Diseases/metabolism, Prions/genetics, Proteasome Endopeptidase Complex/metabolism, Protein Folding, Ubiquitin/metabolism, Ubiquitinated Proteins/metabolism
Identifiers
Local EPrints ID: 474247
URI: http://eprints.soton.ac.uk/id/eprint/474247
ISSN: 0021-9533
PURE UUID: d94e8459-88f7-4839-944f-a2a0cddd1233
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Date deposited: 16 Feb 2023 17:57
Last modified: 17 Mar 2024 04:17
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Author:
Tziona Ben-Gedalya
Author:
Roman Lyakhovetsky
Author:
Yifat Yedidia
Author:
Michal Bejerano-Sagie
Author:
Natalya M Kogan
Author:
Marcela Viviana Karpuj
Author:
Daniel Kaganovich
Author:
Ehud Cohen
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