Neef Daniel W, Jaeger Alex M, Gomez-Pastor Rocio, Willmund Felix, Frydman Judith, Thiele Dennis J
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Department of Biology, Stanford University, Palo Alto, CA 94305, USA.
Cell Rep. 2014 Nov 6;9(3):955-66. doi: 10.1016/j.celrep.2014.09.056. Epub 2014 Oct 30.
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.
热休克转录因子1（HSF1）是一种进化上保守的转录因子，可保护细胞免受蛋白质错误折叠诱导的应激和凋亡。胞质蛋白错误折叠导致HSF1激活的机制尚未阐明。在此，我们证明HSF1直接受TRiC/CCT调控，TRiC/CCT是一种折叠胞质蛋白的核心ATP依赖伴侣蛋白复合物。HSF1的小分子激活剂HSF1A可保护细胞免受应激诱导的凋亡，在体内和体外与TRiC亚基结合，并抑制TRiC活性而不干扰ATP水解。TRiC复合物的基因失活或缺失导致人类HSF1激活，并且HSF1A在体外抑制纯化的TRiC与HSF1之间的直接相互作用。这些结果证明了胞质伴侣蛋白机器与保护细胞免受蛋白毒性的关键转录因子之间存在直接的调控相互作用，为蛋白质折叠中的信号扰动向应激保护转录因子传递提供了机制基础。
