A novel HSF1-mediated death pathway that is suppressed by heat shock proteins
A novel HSF1-mediated death pathway that is suppressed by heat shock proteins
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DOI：
10.1038/sj.emboj.7601370
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发表时间：
2006-10-18
期刊：
影响因子：
11.4
通讯作者：
Nakai, Akira
中科院分区：
文献类型：
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作者：
Hayashida, Naoki;Inouye, Sachiye;Nakai, Akira
热休克反应是对蛋白毒性应激的一种过继反应，主要的热休克转录因子1（HSF 1）被认为通过诱导热休克蛋白（Hsps）来保护细胞免于细胞死亡，热休克蛋白（Hsps）帮助蛋白质折叠并防止蛋白质变性。然而，最近发现，HSF 1也促进雄性生殖细胞的细胞死亡。在这里，我们发现了一个促凋亡Tdag 51（T细胞死亡相关基因51）基因作为HSF 1的直接靶基因。热休克和其他应激诱导不同水平的Hsps和Tdag 51，这取决于细胞类型。热休克蛋白直接绑定到Tdag 51的N-末端普列克底物蛋白同源样（PHL）结构域，并抑制C-末端脯氨酸/谷氨酰胺/组氨酸丰富的结构域的死亡活性。Tdag 51，而不是主要的热休克蛋白，诱导雄性生殖细胞暴露于高温。对Tdag 51缺失睾丸的分析表明，Tdag 51在体内促进热休克诱导的细胞死亡中起重要作用。这些数据表明，蛋白毒性条件下的细胞命运至少是由Hsp和Tdag 51水平之间的平衡决定的，Hsp和Tdag 51水平受HSF 1的不同调节。
Heat shock response is an adoptive response to proteotoxic stress, and a major heat shock transcription factor 1 (HSF1) has been believed to protect cells from cell death by inducing heat shock proteins (Hsps) that assist protein folding and prevent protein denaturation. However, it is revealed recently that HSF1 also promotes cell death of male germ cells. Here, we found a proapoptotic Tdag51 (T-cell death associated gene 51) gene as a direct target gene of HSF1. Heat shock and other stresses induced different levels of Hsps and Tdag51, which depend on cell types. Hsps bound directly to the N-terminal pleckstrin-homology like (PHL) domain of Tdag51, and suppressed death activity of the C-terminal proline/glutamine/histidine-rich domain. Tdag51, but not major Hsps, were induced in male germ cells exposed to high temperatures. Analysis of Tdag51-null testes showed that Tdag51 played substantial roles in promoting heat shock-induced cell death in vivo. These data suggest that cell fate on proteotoxic condition is determined at least by balance between Hsp and Tdag51 levels, which are differently regulated by HSF1.