title: 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.
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.
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Shi
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China; Institute of Molecular Medicine and Genetics and Department of Neurology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine and Genetics and Department of Neurology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Huqiao
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Epidemiology & Biostatistics, School of Public Health, Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Quqin
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Institute of Molecular Medicine and Genetics and Department of Neurology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.affiliation: Institute of Molecular Medicine and Genetics and Department of Neurology, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Luo
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011061:Poly A / Q000378:metabolism*; D039122:Poly(A)-Binding Protein I; D039102:Poly(A)-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D050505:Mutant Proteins; C000608101:PABPN1 protein, mouse; D010455:Peptides; D039122:Poly(A)-Binding Protein I; D039102:Poly(A)-Binding Proteins; D066329:Protein Aggregates; D011061:Poly A; C019529:polyalanine; C112765:tanespimycin; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases