HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

Abstract Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 i...

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Autores principales:	Toshiki Kijima, Thomas L. Prince, Megan L. Tigue, Kendrick H. Yim, Harvey Schwartz, Kristin Beebe, Sunmin Lee, Marek A. Budzynski, Heinric Williams, Jane B. Trepel, Lea Sistonen, Stuart Calderwood, Len Neckers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b5b85ac651e04db4890864d6af7a27c5
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spelling	oai:doaj.org-article:b5b85ac651e04db4890864d6af7a27c52021-12-02T12:33:00ZHSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation10.1038/s41598-018-25404-w2045-2322https://doaj.org/article/b5b85ac651e04db4890864d6af7a27c52018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25404-whttps://doaj.org/toc/2045-2322Abstract Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.Toshiki KijimaThomas L. PrinceMegan L. TigueKendrick H. YimHarvey SchwartzKristin BeebeSunmin LeeMarek A. BudzynskiHeinric WilliamsJane B. TrepelLea SistonenStuart CalderwoodLen NeckersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Toshiki Kijima Thomas L. Prince Megan L. Tigue Kendrick H. Yim Harvey Schwartz Kristin Beebe Sunmin Lee Marek A. Budzynski Heinric Williams Jane B. Trepel Lea Sistonen Stuart Calderwood Len Neckers HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
description	Abstract Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.
format	article
author	Toshiki Kijima Thomas L. Prince Megan L. Tigue Kendrick H. Yim Harvey Schwartz Kristin Beebe Sunmin Lee Marek A. Budzynski Heinric Williams Jane B. Trepel Lea Sistonen Stuart Calderwood Len Neckers
author_facet	Toshiki Kijima Thomas L. Prince Megan L. Tigue Kendrick H. Yim Harvey Schwartz Kristin Beebe Sunmin Lee Marek A. Budzynski Heinric Williams Jane B. Trepel Lea Sistonen Stuart Calderwood Len Neckers
author_sort	Toshiki Kijima
title	HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
title_short	HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
title_full	HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
title_fullStr	HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
title_full_unstemmed	HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation
title_sort	hsp90 inhibitors disrupt a transient hsp90-hsf1 interaction and identify a noncanonical model of hsp90-mediated hsf1 regulation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/b5b85ac651e04db4890864d6af7a27c5
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HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

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