Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism
Gabriel N. Aughey,
Stuart J. Grice,
Qing-Ji Shen,
Yichi Xu,
Chia-Chun Chang,
Ghows Azzam,
Pei-Yu Wang,
Luke Freeman-Mills,
Li-Mei Pai,
Li-Ying Sung,
Jun Yan,
Ji-Long Liu
Affiliations
Gabriel N. Aughey
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
Stuart J. Grice
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
Qing-Ji Shen
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
Yichi Xu
CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Chia-Chun Chang
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan, Republic of China
Ghows Azzam
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
Pei-Yu Wang
Department of Biochemistry, College of Medicine, Chang Gung University, Tao-Yuan, 333, Taiwan, Republic of China
Luke Freeman-Mills
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
Li-Mei Pai
Department of Biochemistry, College of Medicine, Chang Gung University, Tao-Yuan, 333, Taiwan, Republic of China
Li-Ying Sung
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan, Republic of China
Jun Yan
CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Ji-Long Liu
Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom
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.
