Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complex.
In the absence of stress, human heat shock factor 1 (hHSF1) is in its unactivated form. hHSF1 polypeptide is in a dynamic heterocomplex with Hsp90 and is incapable of specifically binding DNA. When cells are stressed, heterocomplex assembly is disrupted. Unbound hHSF1 homotrimerizes, acquires DNA binding activity, and concentrates in the nucleus, but remains transcriptionally inactive. A subsequent reaction converts this inactive, trimeric form into the active, hyperphosphorylated transcription factor. Subsequent to the stressful event, hHSF1 is deactivated and eventually returned to its unactivated form. Evidence is presented herein that trimeric hHSF1 has the propensity to dynamically associate with an Hsp90-immunophilin-p23 complex through its regulatory domain. Formation of this heterocomplex results in repression of the transcriptional activity of trimeric hHSF1. Stress-denatured proteins effectively compete with trimeric hHSF1 for Hsp90-immunophilin-p23 complex, counteracting assembly of the heterocomplex and repression of hHSF1 transcriptional activity. This repression mechanism may be required for a proportional transcriptional response to stress. Formation of the heterocomplex may also represent the first step toward returning the hHSF1 to its unactivated form.
Guo
Y
Y
Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, Florida 33136, USA.
Guettouche
T
T
Fenna
M
M
Boellmann
F
F
Pratt
W B
WB
Toft
D O
DO
Smith
D F
DF
Voellmy
R
R
D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D011485:Protein Binding; D011489:Protein Denaturation; D012097:Repressor Proteins / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4