Hayashida Naoki, Inouye Sachiye, Fujimoto Mitsuaki, Tanaka Yasunori, Izu Hanae, Takaki Eiichi, Ichikawa Hitoshi, Rho Jaerang, Nakai Akira
Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube, Japan.
EMBO J. 2006 Oct 18;25(20):4773-83. doi: 10.1038/sj.emboj.7601370. Epub 2006 Oct 5.
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.
热休克反应是对蛋白质毒性应激的一种适应性反应，人们一直认为主要的热休克转录因子1（HSF1）通过诱导有助于蛋白质折叠并防止蛋白质变性的热休克蛋白（Hsps）来保护细胞免于细胞死亡。然而，最近有研究表明HSF1也会促进雄性生殖细胞的死亡。在此，我们发现促凋亡基因Tdag51（T细胞死亡相关基因51）是HSF1的直接靶基因。热休克和其他应激诱导不同水平的Hsps和Tdag51，这取决于细胞类型。Hsps直接结合到Tdag51的N端类普列克底物蛋白同源（PHL）结构域，并抑制C端富含脯氨酸/谷氨酰胺/组氨酸结构域的死亡活性。在暴露于高温的雄性生殖细胞中会诱导Tdag51的表达，但主要的Hsps则不会。对Tdag51基因敲除小鼠睾丸的分析表明，Tdag51在体内促进热休克诱导的细胞死亡中发挥了重要作用。这些数据表明，在蛋白质毒性条件下细胞的命运至少由Hsp和Tdag51水平之间的平衡决定，而它们受HSF1的调控方式不同。
