title: A direct regulatory interaction between chaperonin TRiC and stress-responsive transcription factor HSF1.
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 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Neef
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Jaeger
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Rocio
authors.initials: R
authors.lastname: Gomez-Pastor
authors.affiliation: Department of Biology, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Willmund
authors.affiliation: Department of Biology, Stanford University, Palo Alto, CA 94305, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: dennis.thiele@duke.edu.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D046912:Multiprotein Complexes; D021122:Protein Subunits; D014157:Transcription Factors; D014415:Tunicamycin