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The Inhibition of Heat Shock Protein 90 Facilitates the Degradation of Poly-Alanine Expanded Poly (A) Binding Protein Nuclear 1 via the Carboxyl Terminus of Heat Shock Protein 70-Interacting Protein
- Source :
- PLoS ONE, PLoS ONE, Vol 10, Iss 9, p e0138936 (2015)
- Publication Year :
- 2015
- Publisher :
- Public Library of Science, 2015.
-
Abstract
- Background Since the identification of poly-alanine expanded poly(A) binding protein nuclear 1 (PABPN1) as the genetic cause of oculopharyngeal muscular dystrophy (OPMD), considerable progress has been made in our understanding of the pathogenesis of the disease. However, the molecular mechanisms that regulate the onset and progression of the disease remain unclear. Results In this study, we show that PABPN1 interacts with and is stabilized by heat shock protein 90 (HSP90). Treatment with the HSP90 inhibitor 17-AAG disrupted the interaction of mutant PABPN1 with HSP90 and reduced the formation of intranuclear inclusions (INIs). Furthermore, mutant PABPN1 was preferentially degraded in the presence of 17-AAG compared with wild-type PABPN1 in vitro and in vivo. The effect of 17-AAG was mediated through an increase in the interaction of PABPN1 with the carboxyl terminus of heat shock protein 70-interacting protein (CHIP). The overexpression of CHIP suppressed the aggregation of mutant PABPN1 in transfected cells. Conclusions Our results demonstrate that the HSP90 molecular chaperone system plays a crucial role in the selective elimination of abnormal PABPN1 proteins and also suggest a potential therapeutic application of the HSP90 inhibitor 17-AAG for the treatment of OPMD.
- Subjects :
- Lactams, Macrocyclic
Ubiquitin-Protein Ligases
lcsh:Medicine
Models, Biological
Poly(A)-Binding Protein I
Poly(A)-Binding Proteins
HSPA4
Protein Aggregates
Heat shock protein
Poly(A)-binding protein
polycyclic compounds
Benzoquinones
Animals
Protein Interaction Domains and Motifs
HSP90 Heat-Shock Proteins
Heat shock
lcsh:Science
Cells, Cultured
Multidisciplinary
HSPA14
biology
Cell Death
Binding protein
lcsh:R
Ubiquitination
Poly(A)-Binding Protein II
Cell biology
Mice, Inbred C57BL
Biochemistry
Proteolysis
biology.protein
lcsh:Q
Mutant Proteins
Peptides
Poly A
Research Article
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 10
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....e5c2ea205cad5f16a75facc8c2706dcb