Histidine-dependent protein methylation is required for compartmentalization of CTP synthase

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. CTPS protein levels remained stable in the presence of histidine during nutrient deprivation, followed by rapid cell growth following nutrient replenishment. Tetramer conformation-based filament formation restricted CTPS enzyme activity duringnutrient deprivation. Furthermore, we demonstrated that filament formation controlled at two levels. Starvation stress/glutamine deficiency activates the GCN2/ATF4/MTHFD2 axis to accelerate the folate cycle in mitochondria for energy homeostasis. In addition, histidine promotes re-methylation of homocysteine by donating one-carbon to the cytosolic folate cycle. CTPS filament formation induced by histidine-mediated methylation maybe a strategy usedby cancer cells to maintain homeostasis and ensure a growth advantage in adverse environments. Cell culture in different medium (DMEM, EBSS and EBSS+Histidine) for 4 h, with two independent experiment