TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway
TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway
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DOI：
10.1074/jbc.m611723200
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发表时间：
2007-05-25
影响因子：
4.8
通讯作者：
Fafournoux, Pierre
中科院分区：
文献类型：
--
作者：
Jousse, Celine;Deval, Christiane;Fafournoux, Pierre
整合应激反应（ISR）是指对多种应激的高度保守反应，这些应激反应集中于转录激活因子4（ATF 4）的诱导。由于不受控制的反应可能会产生有害影响，细胞已经精心制作了几个负反馈回路，削弱了ISR。在本研究中，我们描述了如何诱导人类同源果蝇tribbles（TRB 3）衰减ISR的负反馈机制。为了研究TRB 3在控制ISR中的作用，我们使用氨基酸限制对基因表达的调节作为模型。在氨基酸饥饿时增强的ATF 4产生导致诱导大量靶基因如CHOP（CAAT/增强子结合蛋白同源蛋白）、天冬酰胺合成酶（ASNS）或TRB 3。我们证明TRB 3过表达抑制CHOP和ASNS的转录诱导，而TRB 3沉默诱导这些基因在正常和应激条件下的表达。此外，转录谱实验表明TRB 3影响许多ISR调控基因的表达。我们的研究结果还表明，TRB 3和ATF 4属于相同的蛋白质复合物结合到序列参与的ATF 4依赖的调控基因表达的氨基酸限制。总的来说，我们的数据确定TRB 3作为ATF 4依赖性转录的负反馈调节因子，并参与ISR的精细调节。
The integrated stress response (ISR) is defined as a highly conserved response to several stresses that converge to the induction of the activating transcription factor 4 (ATF4). Because an uncontrolled response may have deleterious effects, cells have elaborated several negative feedback loops that attenuate the ISR. In the present study, we describe how induction of the human homolog of Drosophila tribbles (TRB3) attenuates the ISR by a negative feedback mechanism. To investigate the role of TRB3 in the control of the ISR, we used the regulation of gene expression by amino acid limitation as a model. The enhanced production of ATF4 upon amino acid starvation results in the induction of a large number of target genes like CHOP (CAAT/enhancer-binding protein-homologous protein), asparagine synthetase (ASNS), or TRB3. We demonstrate that TRB3 overexpression inhibits the transcriptional induction of CHOP and ASNS whereas TRB3 silencing induces the expression of these genes both under normal and stressed conditions. In addition, transcriptional profiling experiments show that TRB3 affects the expression of many ISR-regulated genes. Our results also suggest that TRB3 and ATF4 belong to the same protein complex bound to the sequence involved in the ATF4-dependent regulation of gene expression by amino acid limitation. Collectively, our data identify TRB3 as a negative feedback regulator of the ATF4-dependent transcription and participates to the fine regulation of the ISR.