Heat shock transcription factor 1 is required for maintenance of ciliary beating in mice
Heat shock transcription factor 1 is required for maintenance of ciliary beating in mice
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DOI：
10.1074/jbc.m704562200
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发表时间：
2007-12-21
影响因子：
4.8
通讯作者：
Nakai, Akira
中科院分区：
文献类型：
--
作者：
Takaki, Eiichi;Fujimoto, Mitsuaki;Nakai, Akira
热休克转录因子(HSFs)通过调节热休克蛋白的表达来维持蛋白质的动态平衡，特别是在应激条件下。此外，热休克因子通过调节发育相关基因和热休克基因参与细胞分化和发育。在这里，我们展示了出生后HSF1基因缺失的小鼠的慢性鼻窦炎和轻度脑积水，它们分别与粘液纤毛清除和脑脊髓血流受损有关。纤毛搏动分析表明，HSF1基因缺失小鼠的呼吸道上皮、室管膜细胞、输卵管和气管的纤毛搏动幅度显著低于野生型小鼠，纤毛搏动频率低于野生型小鼠。纤毛具有共同的轴突结构，由α-微管和β-微管组成。我们发现在HSF1缺失的小鼠的纤毛中，α-微管蛋白和纤毛β(IV)-微管蛋白显著减少，这与HSP90在HSF1缺失小鼠中的表达减少有关。用格尔达那霉素处理呼吸道上皮后，纤毛搏动迅速减少，且呈剂量依赖关系。此外，Hsp90在物理上与纤毛β(IV)-微管蛋白结合，并且在体外稳定微管蛋白聚合。这些结果表明，HSF1可能通过调节Hsp90的结构性表达来维持出生后小鼠的纤毛搏动，Hsp90对微管蛋白聚合是重要的。
Heat shock transcription factors (HSFs) maintain protein homeostasis through regulating expression of heat shock proteins, especially in stressed conditions. In addition, HSFs are involved in cellular differentiation and development by regulating development-related genes, as well as heat shock genes. Here, we showed chronic sinusitis and mild hydrocephalus in postnatal HSF1-null mice, which are associated with impaired mucociliary clearance and cerebrospinal flow, respectively. Analysis of ciliary beating revealed that the amplitude of the beating was significantly reduced, and ciliary beat frequencies were lower in the respiratory epithelium, ependymal cells, oviduct, and trachea of HSF1-null mice than those of wild-type mice. Cilia possess a common axonema structure composed of microtubules of alpha- and beta-tubulin. We found a marked reduction in alpha- and ciliary beta(iv)-tubulin in the HSF1-null cilia, which is developmentally associated with reduced Hsp90 expression in HSF1-null mice. Treatment of the respiratory epithelium with geldanamycin resulted in rapid reduction of ciliary beating in a dose-dependent manner. Furthermore, Hsp90 was physically associated with ciliary beta(iv)-tubulin, and Hsp90 stabilizes tubulin polymerization in vitro. These results indicate that HSF1 is required to maintain ciliary beating in postnatal mice, probably by regulating constitutive expression of Hsp90 that is important for tubulin polymerization.