title: Heat shock factor 2 is required for maintaining proteostasis against febrile-range thermal stress and polyglutamine aggregation.
abstract: Heat shock response is characterized by the induction of heat shock proteins (HSPs), which facilitate protein folding, and non-HSP proteins with diverse functions, including protein degradation, and is regulated by heat shock factors (HSFs). HSF1 is a master regulator of HSP expression during heat shock in mammals, as is HSF3 in avians. HSF2 plays roles in development of the brain and reproductive organs. However, the fundamental roles of HSF2 in vertebrate cells have not been identified. Here we find that vertebrate HSF2 is activated during heat shock in the physiological range. HSF2 deficiency reduces threshold for chicken HSF3 or mouse HSF1 activation, resulting in increased HSP expression during mild heat shock. HSF2-null cells are more sensitive to sustained mild heat shock than wild-type cells, associated with the accumulation of ubiquitylated misfolded proteins. Furthermore, loss of HSF2 function increases the accumulation of aggregated polyglutamine protein and shortens the lifespan of R6/2 Huntington's disease mice, partly through αB-crystallin expression. These results identify HSF2 as a major regulator of proteostasis capacity against febrile-range thermal stress and suggest that HSF2 could be a promising therapeutic target for protein-misfolding diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube 755-8505, Japan.
authors.forename: Toyohide
authors.initials: T
authors.lastname: Shinkawa
authors.forename: Ke
authors.initials: K
authors.lastname: Tan
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Hayashida
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Eiichi
authors.initials: E
authors.lastname: Takaki
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takii
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Prakasam
authors.forename: Sachiye
authors.initials: S
authors.lastname: Inouye
authors.forename: Valerie
authors.initials: V
authors.lastname: Mezger
authors.forename: Akira
authors.initials: A
authors.lastname: Nakai
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism; D002645:Chickens; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018869:Heat-Shock Response / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D006360:Heat-Shock Proteins; C531390:Hsf2 protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D014157:Transcription Factors; D038203:alpha-Crystallin B Chain; C097188:polyglutamine