Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress
Heterogeneous Nuclear Ribonucleoprotein A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress
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DOI：
10.1091/mbc.e09-04-0296
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发表时间：
2009-09-15
影响因子：
3.3
通讯作者：
Avadhani, Narayan G.
中科院分区：
文献类型：
--
作者：
Guha, Manti;Pan, Hua;Avadhani, Narayan G.
线粒体功能障碍和改变的跨膜电位在广泛的细胞中启动线粒体呼吸应激反应，也称为线粒体逆行反应。线粒体应激反应激活钙调神经磷酸酶，钙调神经磷酸酶调节转录因子，包括一个新的核因子-κ B（NF-κ B B）途径，不同于经典和非经典途径。在这项研究中，使用小干扰RNA介导的mRNA敲低，转录分析和染色质免疫沉淀相结合，我们报告了一个共同的机制，以前建立的应激反应基因组织蛋白酶L，RyR 1和谷氨酸4的调节。应激调节转录涉及NF-κ B（cRel：p50）、C/EBP δ、cAMP反应元件结合蛋白和活化T细胞的核因子之间的协同相互作用。我们发现，这些因素的功能协同作用需要应力激活的异质核核糖核蛋白（hnRNP）A2作为共激活剂。HnRNPA 2主要通过与DNA结合因子的蛋白质-蛋白质相互作用与增强体结合。沉默的hnRNPA 2以及其他DNA结合的签名因子防止应激诱导的转录激活和逆转线粒体DNA耗尽的C2 C12细胞的侵袭性。电子转移链抑制剂诱导的线粒体应激信号传导也涉及hnRNPA 2激活。我们描述了一个共同的机制，线粒体呼吸应激诱导的核靶基因的激活，涉及hnRNPA 2作为转录辅激活因子。
Mitochondrial dysfunction and altered transmembrane potential initiate a mitochondrial respiratory stress response, also known as mitochondrial retrograde response, in a wide spectrum of cells. The mitochondrial stress response activates calcineurin, which regulates transcription factors, including a new nuclear factor-kappa B (NF-kappa B) pathway, different from the canonical and noncanonical pathways. In this study using a combination of small interfering RNA-mediated mRNA knock down, transcriptional analysis, and chromatin immunoprecipitation, we report a common mechanism for the regulation of previously established stress response genes Cathepsin L, RyR1, and Glut4. Stress-regulated transcription involves the cooperative interplay between NF-kappa B (cRel: p50), C/EBP delta, cAMP response element-binding protein, and nuclear factor of activated T cells. We show that the functional synergy of these factors requires the stress-activated heterogeneous nuclear ribonucleoprotein (hnRNP) A2 as a coactivator. HnRNP A2 associates with the enhanceosome, mostly through protein-protein interactions with DNA-bound factors. Silencing of hnRNP A2 as well as other DNA binding signature factors prevents stress-induced transcriptional activation and reverses the invasiveness of mitochondrial DNA-depleted C2C12 cells. Induction of mitochondrial stress signaling by electron transfer chain inhibitors also involved hnRNPA2 activation. We describe a common mechanism of mitochondrial respiratory stress-induced activation of nuclear target genes that involves hnRNP A2 as a transcription coactivator.