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.
Highlights
CTP serves as the building blocks for nucleic acid synthesis, and contributes to the synthesis of membrane phospholipids and protein sialylation (Huang and Graves, 2003; Higgins et al, 2007)
The knockdown efficiency of the indicated genes was verified by Western blotting (Fig. 4F). These results show that mTOR complex 1 (mTORC1) plays a dominant role in controlling CTP synthase (CTPS) cytoophidium assembly
We further investigated the correlation between mechanistic target of rapamycin (mTOR) pathway and CTPS cytoophidium assembly in vivo
Summary
CTP serves as the building blocks for nucleic acid synthesis, and contributes to the synthesis of membrane phospholipids and protein sialylation (Huang and Graves, 2003; Higgins et al, 2007). (Levitzki and Koshland, 1971) It has been demonstrated in a number of studies that CTPS can be assembled into filamentous structures, termed cytoophidia, in several different organisms, including fruit fly, bacteria, yeast and mammalian cells (IngersonMahar et al, 2010; Liu, 2010; Noree et al, 2010; Carcamo et al, 2011; Chen et al, 2011). We observed the presence of CTPS cytoophidia in a variety of human cancer tissues (Chang et al, 2017). To get a better understanding of the regulation of cytoophidium, we used a human cancer cell line and Drosophila as model systems to investigate the regulation of cytoophidium assembly by mTOR. This study links mTOR-S6K1 pathway to the polymerization of the pyrimidine metabolic enzyme CTPS
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