title: Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism.
abstract: The essential metabolic enzyme CTP synthase (CTPsyn) can be compartmentalised to form an evolutionarily-conserved intracellular structure termed the cytoophidium. Recently, it has been demonstrated that the enzymatic activity of CTPsyn is attenuated by incorporation into cytoophidia in bacteria and yeast cells. Here we demonstrate that CTPsyn is regulated in a similar manner in Drosophila tissues in vivo. We show that cytoophidium formation occurs during nutrient deprivation in cultured cells, as well as in quiescent and starved neuroblasts of the Drosophila larval central nervous system. We also show that cytoophidia formation is reversible during neurogenesis, indicating that filament formation regulates pyrimidine synthesis in a normal developmental context. Furthermore, our global metabolic profiling demonstrates that CTPsyn overexpression does not significantly alter CTPsyn-related enzymatic activity, suggesting that cytoophidium formation facilitates metabolic stabilisation. In addition, we show that overexpression of CTPsyn only results in moderate increase of CTP pool in human stable cell lines. Together, our study provides experimental evidence, and a mathematical model, for the hypothesis that inactive CTPsyn is incorporated into cytoophidia.
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Aughey
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Grice
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
authors.forename: Qing-Ji
authors.initials: QJ
authors.lastname: Shen
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yichi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan, Republic of China.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
authors.forename: Ghows
authors.initials: G
authors.lastname: Azzam
authors.affiliation: Department of Biochemistry, College of Medicine, Chang Gung University, Tao-Yuan, 333, Taiwan, Republic of China Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan, Republic of China.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Wang
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
authors.forename: Luke
authors.initials: L
authors.lastname: Freeman-Mills
authors.affiliation: Department of Biochemistry, College of Medicine, Chang Gung University, Tao-Yuan, 333, Taiwan, Republic of China Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan, Republic of China Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan, Republic of China.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Pai
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan, Republic of China Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan, Republic of China.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Sung
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom jilong.liu@dpag.ox.ac.uk.
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Liu
keywords: CTP; CTP synthase; Drosophila; cytoophidium; intracellular compartmentation; neurogenesis