Deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast.
Deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast.
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DOI：
10.1371/journal.pone.0015976
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发表时间：
2011-01-06
期刊：
影响因子：
3.7
通讯作者：
Thiele DJ
中科院分区：
文献类型：
--
作者：
Batista-Nascimento L;Neef DW;Liu PC;Rodrigues-Pousada C;Thiele DJ
热休克转录因子1（HSF 1）在细胞对蛋白毒性应激的反应中起重要作用。在正常生长条件下，HSF1作为无活性单体部分地通过翻译后修饰而被抑制，所述翻译后修饰包括蛋白质乙酰化、类小泛素化和磷酸化。当暴露于应激时，HSF 1同源三聚化，在细胞核中积累，结合DNA，变得过度磷酸化并激活应激反应基因的表达。虽然HSF1和调节其活性的机制已经研究了二十多年，但我们对HSF1调节的理解仍然不完整。由于以前的研究表明，HSF1和热休克反应启动子元件（HSE）通常是结构保守的酵母后生动物，我们已经利用遗传上易处理的芽殖酵母作为一个简单的测定系统，以进一步了解机制，调节人类HSF1通过磷酸化丝氨酸303。我们表明，当人HSF1在酵母中表达时，其在S303的磷酸化被MAP激酶Slt2促进，而不依赖于先前认为是先决条件的在S307的引发事件。此外，我们表明，在酵母和哺乳动物细胞中的S303磷酸化发生的GSK3，激酶主要被认为是负责S303磷酸化的独立。最后，虽然以前的研究表明，S303磷酸化抑制HSF1依赖的反式激活，我们现在表明，S303磷酸化也抑制酵母和哺乳动物细胞中的HSF1多聚化。总之，这些研究表明，酵母细胞将是一个强大的实验工具，破译人类HSF1调控方面的翻译后修饰。
Heat shock transcription factor 1 (HSF1) plays an important role in the cellular response to proteotoxic stresses. Under normal growth conditions HSF1 is repressed as an inactive monomer in part through post-translation modifications that include protein acetylation, sumoylation and phosphorylation. Upon exposure to stress HSF1 homotrimerizes, accumulates in nucleus, binds DNA, becomes hyper-phosphorylated and activates the expression of stress response genes. While HSF1 and the mechanisms that regulate its activity have been studied for over two decades, our understanding of HSF1 regulation remains incomplete. As previous studies have shown that HSF1 and the heat shock response promoter element (HSE) are generally structurally conserved from yeast to metazoans, we have made use of the genetically tractable budding yeast as a facile assay system to further understand the mechanisms that regulate human HSF1 through phosphorylation of serine 303. We show that when human HSF1 is expressed in yeast its phosphorylation at S303 is promoted by the MAP-kinase Slt2 independent of a priming event at S307 previously believed to be a prerequisite. Furthermore, we show that phosphorylation at S303 in yeast and mammalian cells occurs independent of GSK3, the kinase primarily thought to be responsible for S303 phosphorylation. Lastly, while previous studies have suggested that S303 phosphorylation represses HSF1-dependent transactivation, we now show that S303 phosphorylation also represses HSF1 multimerization in both yeast and mammalian cells. Taken together, these studies suggest that yeast cells will be a powerful experimental tool for deciphering aspects of human HSF1 regulation by post-translational modifications.
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