Fat body Ire1 regulates lipid homeostasis through the Xbp1s-FoxO axis in Drosophila
Peng Zhao,
Ping Huang,
Tongfu Xu,
Xiaoxiang Xiang,
Ying Sun,
Jingqi Liu,
Cheng Yan,
Lei Wang,
Jiamei Gao,
Shang Cui,
Xiangdong Wang,
Lixing Zhan,
Haiyun Song,
Jingnan Liu,
Wei Song,
Yong Liu
Affiliations
Peng Zhao
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China
Ping Huang
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Tongfu Xu
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Xiaoxiang Xiang
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China
Ying Sun
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Jingqi Liu
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Cheng Yan
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Lei Wang
Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
Jiamei Gao
School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China
Shang Cui
Department of Cell Biology, Shandong University School of Medicine, Jinan, China, 250012
Xiangdong Wang
Department of Cell Biology, Shandong University School of Medicine, Jinan, China, 250012
Lixing Zhan
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Haiyun Song
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Jingnan Liu
School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China
Wei Song
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China; Corresponding author
Yong Liu
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences; the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China; Corresponding author
Summary: The endoplasmic reticulum (ER)-resident transmembrane protein kinase/RNase Ire1 is a conserved sensor of the cellular unfolded protein response and has been implicated in lipid homeostasis, including lipid synthesis and transport, across species. Here we report a novel catabolic role of Ire1 in regulating lipid mobilization in Drosophila. We found that Ire1 is activated by nutrient deprivation, and, importantly, fat body-specific Ire1 deficiency leads to increased lipid mobilization and sensitizes flies to starvation, whereas fat body Ire1 overexpression results in the opposite phenotypes. Genetic interaction and biochemical analyses revealed that Ire1 regulates lipid mobilization by promoting Xbp1s-associated FoxO degradation and suppressing FoxO-dependent lipolytic programs. Our results demonstrate that Ire1 is a catabolic sensor and acts through the Xbp1s-FoxO axis to hamper the lipolytic response during chronic food deprivation. These findings offer new insights into the conserved Ire1 regulation of lipid homeostasis.
