Journal
CELL REPORTS
Volume 24, Issue 10, Pages 2733-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.08.007
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Funding
- Ministry of Science and Technology, Taiwan [MOST 103-2311-B-182-004-MY3, MOST 106-2811-B-182-002]
- Chang Gung Memorial Hospital, Taiwan [CMRPD1E0271-3]
- Chang Gung Memorial Hospital, Taiwan (Biosignature Research Grant) [CIRPD3B0013]
- Ministry of Education (MOE), Taiwan [EMRPD1G0041]
- Molecular Medicine Research Center, Chang Gung University, from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the MOE in Taiwan
- MRC [MC_UU_12021/3, MC_U137788471] Funding Source: UKRI
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CTP synthase (CTPS) forms compartmentalized filaments in response to substrate availability and environmental nutrient status. However, the physiological role of filaments and mechanisms for filament assembly are not well understood. Here, we provide evidence that CTPS forms filaments in response to histidine influx during glutamine starvation. Tetramer conformation-based filament formation restricts CTPS enzymatic activity during nutrient deprivation. CTPS protein levels remain stable in the presence of histidine during nutrient deprivation, followed by rapid cell growth after stress relief. We demonstrate that filament formation is controlled by methylation and that histidine promotes re-methylation of homocysteine by donating one-carbon intermediates to the cytosolic folate cycle. Furthermore, we find that starvation stress and glutamine deficiency activate the GCN2/ATF4/MTHFD2 axis, which coordinates CTPS filament formation. CTPS filament formation induced by histidine-mediated methylation may be a strategy used by cancer cells to maintain homeostasis and ensure a growth advantage in adverse environments.
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