title: Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells.
abstract: TAR DNA binding protein 43 (TDP-43) is a nuclear protein that has been shown to have altered homeostasis in the form of neuronal nuclear and cytoplasmic aggregates in some familial and almost all cases of sporadic amyotrophic lateral sclerosis as well as 51% of frontotemporal lobar degeneration and 57% of Alzheimer's disease cases. Heat shock proteins (HSPs), such as HSP70, recognize misfolded or aggregated proteins and refold, disaggregate, or turn them over and are upregulated by the master transcription factor heat shock factor 1 (HSF1). Here, we explore the effect of HSF1 overexpression on proteotoxic stress-related alterations in TDP-43 solubility, proteolytic processing, and cytotoxicity. HSF1 overexpression reduced TDP-43-positive puncta concomitantly with upregulating HSP70 and HSP90 protein levels. HSF1 overexpression or pharmacological activation sustained TDP-43 solubility and significantly reduced truncation of TDP-43 in response to inhibition of the proteasome with Z-Leu-Leu-Leu-al, and this was reversed by HSF1 inhibition. HSF1 activation conferred protection against toxicity associated with TDP-43 C-terminal fragments without globally increasing the activity of the ubiquitin proteasome system (UPS) while concomitantly reducing the induction of autophagy, suggesting that HSF1 protection is an early event. In support of this, inhibition of HSP70 ATPase activity further reduced TDP-43 solubility. HSF1 knockout significantly increased TDP-43 insolubility and accelerated TDP-43 fragmentation in response to proteotoxic stress. Overall, this study shows that HSF1 overexpression protects against TDP-43 pathology by upregulation of chaperones, especially HSP70, rather than enhancing autophagy or the UPS during times of proteotoxic stress. © 2016 Wiley Periodicals, Inc.
authors.affiliation: George and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas.|Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas.|Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Lin
authors.affiliation: George and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas.|Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas.|Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas.
authors.forename: Oluwarotimi
authors.initials: O
authors.lastname: Folorunso
authors.affiliation: George and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas.|Department of Neurology, The University of Texas Medical Branch, Galveston, Texas.
authors.forename: Giulio
authors.initials: G
authors.lastname: Taglialatela
authors.affiliation: George and Cynthia Woods Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, Texas.|Sealy Center for Vaccine Development, The University of Texas Medical Branch, Galveston, Texas.|Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas.
authors.forename: Anson
authors.initials: A
authors.lastname: Pierce
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000633:toxicity; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D000076249:Heat Shock Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D012995:Solubility; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; C490017:Hsf1 protein, mouse; C578077:Tardbp protein, mouse
keywords: ALS; Alzheimer's disease; Lou Gehrig's disease; RRID:AB_10979281; RRID:AB_10987450; RRID:AB_1659604; RRID:AB_2039260; RRID:AB_2532125; RRID:AB_2532126; RRID:AB_528498; RRID:AB_637828; heat shock factor 1; heat shock proteins; protein aggregation