Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress
Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress
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DOI：
10.1101/gad.1044503
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发表时间：
2003-02-15
影响因子：
10.5
通讯作者：
Thiele, DJ
中科院分区：
文献类型：
--
作者：
Ahn, SG;Thiele, DJ
真核细胞热休克蛋白（Hsp）基因表达的激活响应于多种细胞应激而发生，包括热休克、过氧化氢、解偶联氧化磷酸化、感染和炎症。生物化学和遗传学研究已经清楚地表明哺乳动物热休克因子1（HSF 1）在应激诱导的热休克蛋白基因表达、抗应激诱导的程序性细胞死亡、胚外发育和其他生物学功能中的关键作用。哺乳动物热休克蛋白基因表达的激活涉及应激诱导的HSF 1从无活性单体转化为DNA结合能力的同源三聚体。虽然热休克蛋白激活是生物学中一个重要的保守过程，但对应激感知和信号传导激活HSF 1的确切机制以及许多不同应激激活HSF 1的机制知之甚少。在这份报告中，我们表明，重组哺乳动物HSF1直接感觉热和过氧化氢组装成一个同源三聚体在一个可逆的和氧化还原调节的方式。这两种应力的传感需要两个半胱氨酸残基内的HSF1 DNA结合结构域，从事氧化还原敏感的二硫键。其中一个或两个半胱氨酸被突变的HSF 1衍生物在应激诱导的三位化和DNA结合、应激诱导的核转位和Hsp基因反式激活以及保护小鼠细胞免于应激诱导的凋亡方面是有缺陷的。热和过氧化氢对HSF1的这种氧化还原依赖性激活建立了哺乳动物HSF1应激激活Hsp基因表达的共同机制。
The activation of eukaryotic heat shock protein (Hsp) gene expression occurs in response to a wide variety of cellular stresses including heat shock, hydrogen peroxide, uncoupled oxidative phosphorylation, infection, and inflammation. Biochemical and genetic studies have clearly demonstrated critical roles for mammalian heat shock factor 1 (HSF1) in stress-inducible Hsp gene expression, resistance to stress-induced programmed cell death, extra-embryonic development, and other biological functions. Activation of mammalian Hsp gene expression involves the stress-inducible conversion of HSF1 from the inactive monomer to the DNA-binding competent homotrimer. Although Hsp activation is a central conserved process in biology, the precise mechanisms for stress sensing and signaling to activate HSF1, and the mechanisms by which many distinct stresses activate HSF1, are poorly understood. In this report we demonstrate that recombinant mammalian HSF1 directly senses both heat and hydrogen peroxide to assemble into a homotrimer in a reversible and redox-regulated manner. The sensing of both stresses requires two cysteine residues within the HSF1 DNA-binding domain that are engaged in redox-sensitive disulfide bonds. HSF1 derivatives in which either or both cysteines were mutated are defective in stress-inducible trinterization and DNA binding, stress-inducible nuclear translocation and Hsp gene trans-activation, and in the protection of mouse cells from stress-induced apoptosis. This redox-dependent activation of HSF1 by heat and hydrogen peroxide establishes a common mechanism in the stress activation of Hsp gene expression by mammalian HSF1.