A Direct Regulatory Interaction between Chaperonin TRiC and Stress-Responsive Transcription Factor HSF1

Abstract

Summary Heat Shock Transcription Factor 1 (HSF1) is an evolutionarily conserved transcription factor that protects cells from protein misfolding-induced stress and apoptosis. The mechanisms by which cytosolic protein misfolding leads to HSF1 activation have not been elucidated. Here we demonstrate that HSF1 is directly regulated by TRiC/CCT, a central ATP-dependent chaperonin complex that folds cytosolic proteins. A small molecule activator of HSF1, HSF1A, protects cells from stress-induced apoptosis, binds TRiC subunits in vivo and in vitro and inhibits TRiC activity without perturbation of ATP hydrolysis. Genetic inactivation or depletion of the TRiC complex results in human HSF1 activation and HSF1A inhibits the direct interaction between purified TRiC and HSF1 in vitro. These results demonstrate a direct regulatory interaction between the cytosolic chaperone machine and a critical transcription factor that protects cells from proteo-toxicity, providing a mechanistic basis for signaling perturbations in protein folding to a stress-protective transcription factor.

Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25

“…Although other molecular chaperones, such as heat shock proteins, could be easily induced by activating HSF1, expression of the eukaryotic chaperonin TRiC hetero-oligomeric complex is not regulated by HSF1 transcriptional activity. However, a recent study has revealed that HSF1 is regulated by TRiC (35). Because TRiC directly interacts with HSF1 and represses its transcriptional activity, disturbance of the interaction results HSF1 target gene expression, such as hsp70.…”

The Biology of Proteostasis in Aging and Disease

“…HSF1A suppresses toxicity in cell and tissue culture models of HD and SCA-3/MJD and appears to activate HSF1 by impairing the activity of TRiC, a recently discovered negative regulator of HSF1. HSF1A treatment blocks the direct interaction between TRiC and HSF1, thereby eliciting an HSR (137, 138). Although the precise mechanism by which F1 activates HSF1 is unknown, F1 treatment increases the expression of chaperones and antioxidant enzymes and markedly suppresses polyQ toxicity in C. elegans and tissue culture models of HD.…”

Rethinking HSF1 in Stress, Development, and Organismal Health

“…The activation and attenuation cycle of HSF1 in the HSR includes at least four steps: (1) De-repression & trimerization: upon cell stress, the influx of misfolded proteins prevents HSP70, HSP90, TRiC and perhaps other chaperones from binding to HSF1 monomers. This alleviates the repression of HSF1 by chaperones and is followed by conversion of the monomer to DNA binding competent trimers [9–11], (2) Translocation to the nucleus: HSF1 can exist either constitutively in the nucleus or in the cytoplasm. Upon protein misfolding, HSF1 translocates to the nucleus and drives transcription [2].…”