A direct regulatory interaction between chaperonin TRiC and stress-responsive transcription factor HSF1

Daniel W. Neef, Alex M. Jaeger, Rocio Gomez-Pastor, Felix Willmund, Judith Frydman, Dennis J. Thiele

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

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 ATPdependent chaperonin complex that folds cytosolic proteins. A small-molecule activator of HSF1, HSF1A, protects cells fromstress-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 andHSF1 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.

Original languageEnglish (US)
Pages (from-to)955-966
Number of pages12
JournalCell reports
Volume9
Issue number3
DOIs
StatePublished - 2014

Bibliographical note

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© 2014 The Authors.

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