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

• HSF1A induces HSF1 and protects cells from proapoptotic stresses
• HSF1A targets the chaperonin TRiC/CCT
• HSF1A perturbs the direct interaction between TRiC/CCT and HSF1
• TRiC-HSF1 interaction links protein misfolding to stress-responsive transcription

SummaryHeat 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 proteotoxicity, providing a mechanistic basis for signaling perturbations in protein folding to a stress-protective transcription factor.

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