Tau protein aggregates inhibit the protein-folding and vesicular trafficking arms of the cellular proteostasis network.
Clathrin-mediated endocytosis
HSC70
HSP27
HSP70
Tau protein (Tau)
chaperone
chaperone competition
heat-shock protein (HSP)
heat-shock protein 90 (Hsp90)
protein aggregation
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
10 05 2019
10 05 2019
Historique:
received:
14
01
2019
revised:
29
03
2019
pubmed:
3
4
2019
medline:
18
12
2019
entrez:
3
4
2019
Statut:
ppublish
Résumé
Tauopathies are a diverse class of neurodegenerative diseases characterized by the formation of insoluble tau aggregates and the loss of cellular function and neuronal death. Tau inclusions have been shown to contain a number of proteins, including molecular chaperones, but the consequences of these entrapments are not well established. Here, using a human cell system for seeding-dependent tau aggregation, we demonstrate that the molecular chaperones heat-shock cognate 71-kDa protein (HSC70)/heat-shock protein 70 (HSP70), HSP90, and J-domain co-chaperones are sequestered by tau aggregates. By employing single-cell analysis of protein-folding and clathrin-mediated endocytosis, we show that both chaperone-dependent cellular activities are significantly impaired by tau aggregation and can be reversed by treatment with small-molecule regulators of heat-shock transcription factor 1 (HSF1) proteostasis that induce the expression of cytosolic chaperones. These results reveal that the sequestration of cytoplasmic molecular chaperones by tau aggregates interferes with two arms of the proteostasis network, likely having profound negative consequences for cellular function.
Identifiants
pubmed: 30936201
pii: S0021-9258(20)35481-8
doi: 10.1074/jbc.RA119.007527
pmc: PMC6514629
doi:
Substances chimiques
HSC70 Heat-Shock Proteins
0
HSF1 protein, human
0
HSP90 Heat-Shock Proteins
0
HSPA8 protein, human
0
Heat Shock Transcription Factors
0
tau Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7917-7930Subventions
Organisme : NIA NIH HHS
ID : RF1 AG057296
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG026647
Pays : United States
Organisme : NIH HHS
ID : S10 OD023681
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG059579
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054409
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG054407
Pays : United States
Informations de copyright
© 2019 Yu et al.
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