A sphingolipid-mTORC1 nutrient-sensing pathway regulates animal development by an intestinal peroxisome relocation-based gut-brain crosstalk
Na Li,
Beilei Hua,
Qing Chen,
Fukang Teng,
Meiyu Ruan,
Mengnan Zhu,
Li Zhang,
Yinbo Huo,
Hongqin Liu,
Min Zhuang,
Huali Shen,
Huanhu Zhu
Affiliations
Na Li
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100000, China
Beilei Hua
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Qing Chen
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Fukang Teng
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Meiyu Ruan
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Mengnan Zhu
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100000, China
Li Zhang
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Yinbo Huo
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100000, China
Hongqin Liu
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Min Zhuang
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Huali Shen
Institutes of Biomedical Sciences, Department of Systems Biology for Medicine and School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Huanhu Zhu
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding author
Summary: The mTOR-dependent nutrient-sensing and response machinery is the central hub for animals to regulate their cellular and developmental programs. However, equivalently pivotal nutrient and metabolite signals upstream of mTOR and developmental-regulatory signals downstream of mTOR are not clear, especially at the organism level. We previously showed glucosylceramide (GlcCer) acts as a critical nutrient and metabolite signal for overall amino acid levels to promote development by activating the intestinal mTORC1 signaling pathway. Here, through a large-scale genetic screen, we find that the intestinal peroxisome is critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, GlcCer deficiency, inactive mTORC1, or prolonged starvation relocates intestinal peroxisomes closer to the apical region in a kinesin- and microtubule-dependent manner. Those apical accumulated peroxisomes further release peroxisomal-β-oxidation-derived glycolipid hormones that target chemosensory neurons and downstream nuclear hormone receptor DAF-12 to arrest the animal development. Our data illustrate a sophisticated gut-brain axis that predominantly orchestrates nutrient-sensing-dependent development in animals.
