Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing.
Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing.
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DOI：
10.1091/mbc.e17-06-0418
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发表时间：
2018-01-01
影响因子：
3.3
通讯作者：
Reiling JH
中科院分区：
文献类型：
--
作者：
Baumann J;Ignashkova TI;Chirasani SR;Ramírez-Peinado S;Alborzinia H;Gendarme M;Kuhnigk K;Kramer V;Lindemann RK;Reiling JH
用高尔基体破坏化合物处理的细胞的转录组学分析显示，包括几种剪接体组分的一些靶基因由ELK 1、GABPA和ETS 1控制，其活性由MEK/ERK信号调节。此外，布雷菲德菌素A和golgicide A导致增加剪接的促凋亡MCL 1-S亚型。分泌途径是细胞内稳态的主要决定因素。虽然对分泌应激信号的研究迄今为止主要集中在内质网（ER）上，但新出现的数据表明高尔基体本身作为能够启动应激反应的重要信号枢纽。为了系统地确定新的高尔基体应激介质，我们进行了转录组学分析的细胞暴露于三种不同的药理学化合物，已知引起高尔基体片段：布雷菲德菌素A，golgicide A，莫能菌素。随后的基因集富集分析揭示了ETS家族转录因子ELK 1、GABPA/B和ETS 1对化合物处理后基因表达控制的显着贡献。高尔基体应激的诱导导致ETS上游激酶MEK 1/2和ERK 1/2的晚期激活，从而增强ETS因子活性和ETS家族靶基因的转录，这些靶基因与剪接体功能和通过选择性MCL 1剪接诱导细胞死亡相关。使用功能丧失和功能获得实验的进一步遗传分析表明，这些转录因子平行运作。
Transcriptomic profiling of cells treated with Golgi-disrupting compounds reveals that some target genes including several spliceosome components are controlled by ELK1, GABPA, and ETS1, the activity of which is regulated by MEK/ERK signaling. Furthermore, brefeldin A and golgicide A cause increased splicing of the proapoptotic MCL1-S isoform. The secretory pathway is a major determinant of cellular homoeostasis. While research into secretory stress signaling has so far mostly focused on the endoplasmic reticulum (ER), emerging data suggest that the Golgi itself serves as an important signaling hub capable of initiating stress responses. To systematically identify novel Golgi stress mediators, we performed a transcriptomic analysis of cells exposed to three different pharmacological compounds known to elicit Golgi fragmentation: brefeldin A, golgicide A, and monensin. Subsequent gene-set enrichment analysis revealed a significant contribution of the ETS family transcription factors ELK1, GABPA/B, and ETS1 to the control of gene expression following compound treatment. Induction of Golgi stress leads to a late activation of the ETS upstream kinases MEK1/2 and ERK1/2, resulting in enhanced ETS factor activity and the transcription of ETS family target genes related to spliceosome function and cell death induction via alternate MCL1 splicing. Further genetic analyses using loss-of-function and gain-of-function experiments suggest that these transcription factors operate in parallel.