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

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: Kijima Toshiki, Prince Thomas L., Tigue Megan L., Yim Kendrick H., Schwartz Harvey, Beebe Kristin, Lee Sunmin, Budzynski Marek A., Williams Heinric, Trepel Jane B., Sistonen Lea, Calderwood Stuart, Neckers Len
Förläggare: Springer Nature Limited
Publiceringsår: 2018
Tidskrift: Scientific Reports
Volym: 8


Abstrakt

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.


Nyckelord

heat shock factor 1, heat shock protein 70, heat shock protein (HSP), HEAT SHOCK TRANSCRIPTION FACTORS


Dokument


Senast uppdaterad 2019-23-08 vid 05:15