Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Cell Rep. 2019 Nov 5;29(6):1645-1659.e9. doi: 10.1016/j.celrep.2019.09.084.
Molecular chaperones such as heat-shock proteins (HSPs) help in protein folding. Their function in the cytosol has been well studied. Notably, chaperones are also present in the nucleus, a compartment where proteins enter after completing de novo folding in the cytosol, and this raises an important question about chaperone function in the nucleus. We performed a systematic analysis of the nuclear pool of heat-shock protein 90. Three orthogonal and independent analyses led us to the core functional interactome of HSP90. Computational and biochemical analyses identify host cell factor C1 (HCFC1) as a transcriptional regulator that depends on HSP90 for its stability. HSP90 was required to maintain the expression of HCFC1-targeted cell-cycle genes. The regulatory nexus between HSP90 and the HCFC1 module identified in this study sheds light on the relevance of chaperones in the transcription of cell-cycle genes. Our study also suggests a therapeutic avenue of combining chaperone and transcription inhibitors for cancer treatment.
分子伴侣，如热休克蛋白（HSPs），有助于蛋白质折叠。它们在细胞质中的功能已得到充分研究。值得注意的是，伴侣也存在于细胞核中，蛋白质在细胞质中完成从头折叠后进入细胞核的一个隔室，这就提出了一个关于核内伴侣功能的重要问题。我们对热休克蛋白 90 的核池进行了系统分析。三种正交且独立的分析使我们得出 HSP90 的核心功能相互作用组。计算和生化分析确定宿主细胞因子 C1（HCFC1）是一种转录调节剂，其稳定性依赖于 HSP90。HSP90 对于维持 HCFC1 靶向细胞周期基因的表达是必需的。本研究中鉴定的 HSP90 和 HCFC1 模块之间的调节枢纽阐明了伴侣在细胞周期基因转录中的相关性。我们的研究还为结合伴侣和转录抑制剂治疗癌症提供了一种治疗途径。
