In response to stress, heat shock factor 1 (HSP1) acquires rapid DNA b
inding and transient transcriptional activity while undergoing conform
ational transition from an inert non-DNA-binding monomer to active fun
ctional trimers. Attenuation of the inducible transcriptional response
occurs during heat shock or upon recovery at non-stress conditions an
d involves dissociation of the HSF1 trimer and loss of activity. We ha
ve used the hydrophobic repeats of the HSF1 trimerization domain in th
e yeast two-hybrid protein interaction assay to identify heat shock fa
ctor binding protein 1 (HSBP1), a novel, conserved, 76-amino-acid prot
ein that contains two extended arrays of hydrophobic repeats that inte
ract with the HSF1 heptad repeats. HSBP1 is nuclear-localized and inte
racts in vivo with the active trimeric state of HSF1 that appears duri
ng heat shack. During attenuation of HSF1 to the inert monomer, HSBP1
associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activ
ity, and overexpression of HSBP1 in mammalian cells represses the tran
sactivation activity of HSF1. To establish a biological role for HSBP1
, the homologous Caenorhabditis elegans protein was overexpressed in b
ody wall muscle cells and was shown to block activation of the heat sh
ock response from a heat shock promoter-reporter construct. Alteration
in the level of HSBP1 expression in C. elegans has severe effects on
survival of the animals after thermal and chemical stress, consistent
with a role for HSBP1 as a negative regulator of the heat shock respon
se.