Coupling of COPII vesicle trafficking to nutrient availability by the IRE1α-XBP1s axis
Coupling of COPII vesicle trafficking to nutrient availability by the IRE1α-XBP1s axis
复制标题
IRE1 α-XBP1s 轴将 COPII 囊泡运输与营养可用性耦合
DOI：
10.1073/pnas.1814480116
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发表时间：
2019-06-11
影响因子：
11.1
通讯作者：
Gan, Zhenji
中科院分区：
文献类型：
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作者：
Liu, Lin;Cai, Jie;Gan, Zhenji
细胞质外壳蛋白复合物-II（COPII）是进化上保守的机制，是蛋白质和脂质货物的有效运输所必需的。然而，如何调节COPII机制以满足营养状态改变时的代谢需求仍然在很大程度上未被探索。在这里，我们表明，COPII囊泡贩运的动态变化平行的转录因子X盒结合蛋白1（XBP 1 s），一个关键的转录因子在处理细胞内质网（ER）的压力在活细胞和小鼠肝脏的生理波动的营养物质的可用性激活。使用活细胞成像方法，我们证明了XBP 1 s足以促进COPII依赖的运输，介导营养刺激作用。染色质免疫沉淀（ChIP）结合高通量DNA测序（ChIP-seq）和RNA测序分析显示，营养信号诱导COPII交通相关基因启动子的动态XBP 1 s占用，从而驱动COPII介导的运输过程。肌醇需要酶Ia（IRE 1 α）-XBP 1 s信号传导分支的肝脏特异性破坏导致COPII囊泡运输减少。在缺乏肝脏IRE 1的小鼠中，XBP 1的重新激活恢复了COPII介导的脂蛋白分泌，并逆转了脂肪肝和低脂血症表型。因此，我们的研究结果证明了一个以前不受重视的机制，在肝脏蛋白质和脂质运输的代谢控制：IRE 1 α-XBP 1 s轴功能作为一个营养传感调节联系，整合营养状态和COPII囊泡运输。
The cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII vesicle trafficking parallel the activation of transcription factor X-box binding protein 1 (XBP1s), a critical transcription factor in handling cellular endoplasmic reticulum (ER) stress in both live cells and mouse livers upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent trafficking, mediating the nutrient stimulatory effects. Chromatin immunoprecipitation (ChIP) coupled with high-throughput DNA sequencing (ChIP-seq) and RNA-sequencing analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII traffic-related genes, thereby driving the COPII-mediated trafficking process. Liver-specific disruption of the inositol-requiring enzyme la (IRE1 alpha)-XBP1s signaling branch results in diminished COPII vesicle trafficking. Reactivation of XBP1s in mice lacking hepatic IRE1 restores COPII-mediated lipoprotein secretion and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid trafficking: The IRE1 alpha-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking.