A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens.
A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens.
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DOI：
10.1038/ncb2865
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发表时间：
2013-12
影响因子：
21.3
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中科院分区：
文献类型：
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用布雷菲德菌素A（BFA）处理细胞会阻断分泌囊泡运输并导致高尔基体塌陷。为了更深入地了解介导BFA毒性的细胞机制，我们进行了全基因组单倍体遗传筛选，鉴定了小G蛋白ADP-核糖基化因子4（ARF 4）。在BFA存在的情况下，ARF 4耗竭保留了活力、高尔基体完整性和货物运输，这些作用取决于鸟嘌呤核苷酸交换因子GBF 1和其他ARF亚型，包括ARF 1和ARF 5。ARF 4敲除细胞显示对包括沙眼衣原体和福氏志贺菌在内的几种人类病原体的抗性增加。此外，当细胞暴露于几种高尔基体干扰剂时，ARF 4表达被诱导，并且需要CREB 3/Luman转录因子，其下调模拟ARF 4损失。因此，我们已经发现了CREB 3-ARF 4信号级联，这可能是高尔基体应激反应的一部分，刺激损害高尔基体的能力。
Treatment of cells with Brefeldin A (BFA) blocks secretory vesicle transport and causes a collapse of the Golgi apparatus. To gain more insight into the cellular mechanisms mediating BFA toxicity, we conducted a genome-wide haploid genetic screen that led to the identification of the small G protein ADP-ribosylation factor 4 (ARF4). ARF4 depletion preserves viability, Golgi integrity and cargo trafficking in the presence of BFA, and these effects depend on the guanine nucleotide exchange factor GBF1 and other ARF isoforms including ARF1 and ARF5. ARF4 knockdown cells show increased resistance to several human pathogens including Chlamydia trachomatis and Shigella flexneri. Furthermore, ARF4 expression is induced when cells are exposed to several Golgi-disturbing agents and requires the CREB3/Luman transcription factor whose downregulation mimics ARF4 loss. Thus, we have uncovered a CREB3–ARF4 signaling cascade that may be part of a Golgi stress response set in motion by stimuli compromising Golgi capacity.