Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway
Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway
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DOI：
10.1128/mcb.20.8.2670-2675.2000
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发表时间：
2000-04-01
影响因子：
5.3
通讯作者：
Sistonen, L
中科院分区：
文献类型：
--
作者：
Pirkkala, L;Alastalo, TP;Sistonen, L
蛋白酶体介导的蛋白质降解机制的抑制是一种有效的应激刺激，其导致泛素化蛋白的积累和热休克蛋白（Hsps）的表达增加。热休克蛋白通过其公认的分子伴侣特性在细胞内环境稳定和保护中发挥关键作用。诱导型热休克蛋白的表达受热休克转录因子（HSFs）的调控。在哺乳动物HSFs中，HSF1在热诱导应激基因表达的调节中起重要作用，而HSF2在应激反应中的功能尚不清楚。最近的研究表明，HSF1和HSF2在泛素-蛋白酶体途径的下调过程中受到影响（Y。Kawazoe等人，EUR. 255：356 - 362，1998; A.马修等人，摩尔cell.，18：5091 - 5098，1998; D. Kim等人，Biochem，Biophys，Res.Commun，254：264 - 268，1999）。然而，迄今为止，没有明确的证据已经提出，是否需要一个单一的特定的HSF或NSF家族的多个成员的热休克基因的转录诱导时，蛋白酶体活性下调。因此，通过使用功能丧失和功能获得策略，我们研究了哺乳动物HSFs在调节泛素-蛋白酶体介导的应激反应中的特定作用。在这里，我们证明，HSF1，而不是HSF2，是必不可少的，足以上调Hsp70的表达在下调的泛素蛋白水解途径。我们认为HSF1的特异性可能是疾病发病机制中与泛素依赖性蛋白酶体功能异常相关的重要治疗靶点。
Inhibition of proteasome-mediated protein degradation machinery is a potent stress stimulus that causes accumulation of ubiquitinated proteins and increased expression of heat shock proteins (Hsps). Hsps play pivotal roles in homeostasis and protection in a cell, through their well-recognized properties as molecular chaperones. The inducible Hsp expression is regulated by the heat shock transcription factors (HSFs). Among mammalian HSFs, HSF1 has been shown to be important for regulation of the heat-induced stress gene expression, whereas the function of HSF2 in stress response is unclear. Recent reports have suggested that both HSF1 and HSF2 are affected during down-regulation of ubiquitin-proteasome pathway (Y. Kawazoe et al., Eur. J. Biochem. 255:356-362, 1998; A. Mathew et al., Mol. Cell. Biol, 18:5091-5098, 1998; D. Kim et al., Biochem, Biophys, Res. Commun, 254:264-268, 1999). To date, however, no unambiguous evidence has been presented as to whether a single specific HSF or multiple members of the NSF family are required for transcriptional induction of heat shock genes when proteasome activity is down-regulated. Therefore, by using loss-of-function and gain-of-function strategies, we investigated the specific roles of mammalian HSFs in regulation of the ubiquitin-proteasome-mediated stress response. Here we demonstrate that HSF1, but not HSF2, is essential and sufficient for up-regulation of Hsp70 expression during down-regulation of the ubiquitin proteolytic pathway. We propose that specificity of HSF1 could be an important therapeutic target during disease pathogenesis associated with abnormal ubiquitin-dependent proteasome function.