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

Chao Shi, Xuan Huang, Bin Zhang, Dan Zhu, Huqiao Luo, Quqin Lu, Wencheng Xiong, Lin Mei, Shiwen Luo

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 beenmade 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.

Original languageEnglish (US)
Article numbere0138936
JournalPloS one
Volume10
Issue number9
DOIs
StatePublished - Sep 28 2015

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Poly(A)-Binding Protein II
HSP90 Heat-Shock Proteins
HSP70 Heat-Shock Proteins
tanespimycin
Alanine
alanine
binding proteins
Degradation
degradation
Oculopharyngeal Muscular Dystrophy
Proteins
proteins
muscular dystrophy
mutants
Poly(A)-Binding Proteins
Intranuclear Inclusion Bodies
Molecular Chaperones
molecular chaperones
Nuclear Proteins
heat-shock protein 70

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

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. / Shi, Chao; Huang, Xuan; Zhang, Bin; Zhu, Dan; Luo, Huqiao; Lu, Quqin; Xiong, Wencheng; Mei, Lin; Luo, Shiwen.

In: PloS one, Vol. 10, No. 9, e0138936, 28.09.2015.

Research output: Contribution to journalArticle

Shi, Chao ; Huang, Xuan ; Zhang, Bin ; Zhu, Dan ; Luo, Huqiao ; Lu, Quqin ; Xiong, Wencheng ; Mei, Lin ; Luo, Shiwen. / 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. In: PloS one. 2015 ; Vol. 10, No. 9.
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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 beenmade 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.",
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