TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death
TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death
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DOI：
10.1038/sj.emboj.7600596
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发表时间：
2005-03-23
期刊：
影响因子：
11.4
通讯作者：
Hayashi, H
中科院分区：
文献类型：
--
作者：
Ohoka, N;Yoshii, S;Hayashi, H
C/EBP同源蛋白（CHOP）是一种应激诱导的核蛋白，对程序性细胞死亡和再生的发展至关重要;然而，其功能的调控尚未得到很好的表征。Slbo是C/EBP（CCAAT/增强子结合蛋白）的果蝇同源物，被证明是不稳定的。在这里，我们确定TRB 3为人类的tribbles直系同源物，其与CHOP相关以抑制CHOP依赖的反式激活。TRB 3在各种形式的内质网应激下诱导表达的时间晚于CHOP。衣霉素处理增强TRB 3启动子活性，而显性负性形式的CHOP抑制衣霉素诱导的激活。此外，TRB 3启动子中的衣霉素反应区含有与CHOP结合位点重叠的氨基酸反应元件，CHOP和ATF 4协同激活该启动子活性。内源性ATF 4或CHOP表达的敲低显著抑制衣霉素诱导的TRB 3诱导。此外，TRB 3表达的敲低降低了ER应激依赖性细胞死亡。这些结果表明，TRB 3是CHOP/ATF 4的一个新靶点，通过抑制CHOP/ATF 4功能下调其自身的诱导作用，并且在ER应激期间参与CHOP依赖性细胞死亡。
C/EBP homologous protein ( CHOP) is a stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration; however, the regulation of its function has not been well characterized. Slbo, a Drosophila homolog of C/EBP (CCAAT/enhancer binding protein), was shown to be unstabilized by tribbles. Here, we identified TRB3 as a tribbles ortholog in humans, which associated with CHOP to suppress the CHOP-dependent transactivation. TRB3 is induced by various forms endoplasmic reticulum ( ER) stress later than CHOP. Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation. In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity. Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction. Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death. These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress.