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Coupling of COPII vesicle trafficking to nutrient availability by the IRE1?-XBP1s axis.


ABSTRACT: 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 1? (IRE1?)-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?-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking.

SUBMITTER: Liu L 

PROVIDER: S-EPMC6575159 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Coupling of COPII vesicle trafficking to nutrient availability by the IRE1α-XBP1s axis.

Liu Lin L   Cai Jie J   Wang Huimin H   Liang Xijun X   Zhou Qian Q   Ding Chenyun C   Zhu Yuangang Y   Fu Tingting T   Guo Qiqi Q   Xu Zhisheng Z   Xiao Liwei L   Liu Jing J   Yin Yujing Y   Fang Lei L   Xue Bin B   Wang Yan Y   Meng Zhuo-Xian ZX   He Aibin A   Li Jian-Liang JL   Liu Yong Y   Chen Xiao-Wei XW   Gan Zhenji Z  

Proceedings of the National Academy of Sciences of the United States of America 20190523 24


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 handli  ...[more]

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