mTOR-S6K1 pathway mediates cytoophidium assembly

Zhe Sun^a,
Ji-Long Liu^{a, b
, ,}

a.
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
b.
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom

More Information

Corresponding author: E-mail address: jilong.liu@dpag.ox.ac.uk (Ji-Long Liu)

摘要

- /
- /
- /
Abstract: CTP synthase (CTPS), the rate-limiting enzyme in de novo CTP biosynthesis, has been demonstrated to assemble into evolutionarily conserved filamentous structures, termed cytoophidia, in Drosophila, bacteria, yeast and mammalian cells. However, the regulation and function of the cytoophidium remain elusive. Here, we provide evidence that the mechanistic target of rapamycin (mTOR) pathway controls cytoophidium assembly in mammalian and Drosophila cells. In mammalian cells, we find that inhibition of mTOR pathway attenuates cytoophidium formation. Moreover, CTPS cytoophidium assembly appears to be dependent on the mTOR complex 1 (mTORC1) mainly. In addition, knockdown of the mTORC1 downstream target S6K1 can inhibit cytoophidium formation, while overexpression of the constitutively active S6K1 reverses mTOR knockdown-induced cytoophidium disassembly. Finally, reducing mTOR protein expression results in a decrease of the length of cytoophidium in Drosophila follicle cells. Therefore, our study connects CTPS cytoophidium formation with the mTOR signaling pathway.
- mTOR /
- Cytoophidium /
- CTP synthase /
- Colorectal cancer cell

HTML全文

参考文献(51)

[1]	Aughey, G.N., Grice, S.J., Liu, J.L. PLoS Genet., 12 (2016),p. e1005867
[2]	Aughey, G.N., Grice, S.J., Shen, Q.J. et al. Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism Biol. Open, 3 (2014),pp. 1045-1056
[3]	Azzam, G., Liu, J.L. PLoS Genet., 9 (2013),p. e1003256
[4]	Barry, R.M., Bitbol, A.F., Lorestani, A. et al. Large-scale filament formation inhibits the activity of CTP synthetase eLife, 3 (2014),p. e03638
[5]	Ben-Sahra, I., Howell, J.J., Asara, J.M. et al. Science, 339 (2013),pp. 1323-1328
[6]	Ben-Sahra, I., Hoxhaj, G., Ricoult, S.J.H. et al. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle Science, 351 (2016),pp. 728-733
[7]	Carcamo, W.C., Satoh, M., Kasahara, H. et al. Induction of cytoplasmic rods and rings structures by inhibition of the CTP and GTP synthetic pathway in mammalian cells PLoS One, 6 (2011),p. e29690
[8]	Chang, C.C., Jeng, Y.M., Peng, M. et al. CTP synthase forms the cytoophidium in human hepatocellular carcinoma Exp. Cell Res., 361 (2017),pp. 292-299
[9]	Chang, Y.F., Martin, S.S., Baldwin, E.P. et al. Phosphorylation of human CTP synthetase 1 by protein kinase C: identification of Ser(462) and Thr(455) as major sites of phosphorylation J. Biol. Chem., 282 (2007),pp. 17613-17622
[10]	Chen, K., Zhang, J., Tastan, O.Y. et al. J. Genet. Genomics., 38 (2011),pp. 391-402
[11]	Choi, M.G., Park, T.S., Carman, G.M. J. Biol. Chem., 278 (2003),pp. 23610-23616
[12]	Earhart, R.H., Amato, D.J., Chang, A.Y. et al. Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas Invest. N. Drugs, 8 (1990),pp. 113-119
[13]	Ellims, P.H., Gan, T.E., Medley, G. Cytidine triphosphate synthetase activity in lymphoproliferative disorders Cancer Res., 43 (1983),pp. 1432-1435
[14]	Falkson, G., Cnaan, A., Simson, I.W. et al. A randomized phase II study of acivicin and 4'deoxydoxorubicin in patients with hepatocellular carcinoma in an Eastern Cooperative Oncology Group study Am. J. Clin. Oncol., 13 (1990),pp. 510-515
[15]	Fingar, D.C., Salama, S., Tsou, C. et al. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E Genes Dev., 16 (2002),pp. 1472-1487
[16]	Grabiner, B.C., Nardi, V., Birsoy, K. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity Cancer Discov., 4 (2014),pp. 554-563
[17]	Han, G.S., Sreenivas, A., Choi, M.G. et al. J. Biol. Chem., 280 (2005),pp. 38328-38336
[18]	Higgins, M.J., Graves, P.R., Graves, L.M. Regulation of human cytidine triphosphate synthetase 1 by glycogen synthase kinase 3 J. Biol. Chem., 282 (2007),pp. 29493-29503
[19]	Huang, M., Graves, L.M. Cell. Mol. Life Sci., 60 (2003),pp. 321-336
[20]	Huang, Y., Wang, J.J., Ghosh, S. et al. Critical roles of CTP synthase N-terminal in cytoophidium assembly Exp. Cell Res., 354 (2017),pp. 122-133
[21]	Ingerson-Mahar, M., Briegel, A., Werner, J.N. et al. The metabolic enzyme CTP synthase forms cytoskeletal filaments Nat. Cell Biol., 12 (2010),pp. 739-746
[22]	Julien, L.A., Carriere, A., Moreau, J. et al. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling Mol. Cell. Biol., 30 (2010),pp. 908-921
[23]	Kizaki, H., Williams, J.C., Morris, H.P. et al. Increased cytidine 5'-triphosphate synthetase activity in rat and human tumors Cancer Res., 40 (1980),pp. 3921-3927
[24]	Levitzki, A., Cytidine triphosphate synthetase. Covalent intermediates and mechanisms of action Biochemistry, 10 (1971),pp. 3365-3371
[25]	Liu, J.L. J. Genet. Genomics., 37 (2010),pp. 281-296
[26]	Liu, J.L. The cytoophidium and its kind: filamentation and compartmentation of metabolic enzymes Annu. Rev. Cell Dev. Biol., 32 (2016),pp. 349-372
[27]	Lloyd, A.C. The regulation of cell size Cell, 154 (2013),pp. 1194-1205
[28]	Lynch, E.M., Hicks, D.R., Shepherd, M. et al. Human CTP synthase filament structure reveals the active enzyme conformation Nat. Struct. Mol. Biol., 24 (2017),pp. 507-514
[29]	Lynch, G., Kemeny, N., Casper, E. Phase II evaluation of DON (6-diazo-5-oxo-L-norleucine) in patients with advanced colorectal carcinoma Am. J. Clin. Oncol., 5 (1982),pp. 541-543
[30]	Maroun, J.A., Stewart, D.J., Verma, S. et al. Phase I study of acivicin and cisplatin in non-small-cell lung cancer. A National Cancer Institute of Canada study Am. J. Clin. Oncol., 13 (1990),pp. 401-404
[31]	Noree, C., Monfort, E., Shiau, A.K. et al. Common regulatory control of CTP synthase enzyme activity and filament formation Mol. Biol. Cell, 25 (2014),pp. 2282-2290
[32]	Noree, C., Sato, B.K., Broyer, R.M. et al. J. Cell Biol., 190 (2010),pp. 541-551
[33]	Park, T.S., O'Brien, D.J., Carman, G.M. J. Biol. Chem., 278 (2003),pp. 20785-20794
[34]	Park, T.S., Ostrander, D.B., Pappas, A. et al. Biochemistry, 38 (1999),pp. 8839-8848
[35]	Robitaille, A.M., Christen, S., Shimobayashi, M. et al. Science, 339 (2013),pp. 1320-1323
[36]	Rubin, J., Sorensen, S., Schutt, A.J. et al. A phase II study of 6-diazo-5-oxo-L-norleucine (DON, NSC-7365) in advanced large bowel carcinoma Am. J. Clin. Oncol., 6 (1983),pp. 325-326
[37]	Sarbassov, D.D., Ali, S.M., Sengupta, S. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB Mol. Cell, 22 (2006),pp. 159-168
[38]	Sarbassov, D.D., Guertin, D.A., Ali, S.M. et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Science, 307 (2005),pp. 1098-1101
[39]	Sato, T., Nakashima, A., Guo, L. et al. Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer Oncogene, 29 (2010),pp. 2746-2752
[40]	Saxton, R.A., Sabatini, D.M. mTOR signaling in growth, metabolism, and disease Cell, 169 (2017),pp. 361-371
[41]	Schmidt, T.T., Reyes, G., Gries, K. et al. Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis Proc. Natl. Acad. Sci. U. S. A., 114 (2017),pp. E4442-E4451
[42]	Strochlic, T.I., Stavrides, K.P., Thomas, S.V. et al. EMBO Rep., 15 (2014),pp. 1184-1191
[43]	Traut, T.W. Physiological concentrations of purines and pyrimidines Mol. Cell. Biochem., 140 (1994),pp. 1-22
[44]	Treins, C., Warne, P.H., Magnuson, M.A. et al. Rictor is a novel target of p70 S6 kinase-1 Oncogene, 29 (2010),pp. 1003-1016
[45]	Valvezan, A.J., Turner, M., Belaid, A. et al. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability Cancer Cell, 32 (2017),pp. 624-638 e625
[46]	van den Berg, A.A., van Lenthe, H., Busch, S. et al. Eur. J. Biochem., 216 (1993),pp. 161-167
[47]	Wang, P.Y., Lin, W.C., Tsai, Y.C. et al. Genetics, 201 (2015),pp. 1511-1523
[48]	Weber, G., Lui, M.S., Takeda, E. et al. Enzymology of human colon tumors Life Sci., 27 (1980),pp. 793-799
[49]	Williams, J.C., Kizaki, H., Weber, G. et al. Increased CTP synthetase activity in cancer cells Nature, 271 (1978),pp. 71-73
[50]	Willoughby, L.F., Schlosser, T., Manning, S.A. et al. Dis. Model. Mech., 6 (2013),pp. 521-529
[51]	Zhang, H., Stallock, J.P., Ng, J.C. et al. Genes Dev., 14 (2000),pp. 2712-2724