Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase

Wei Cheng Lin, Archan Chakraborty, Shih Chia Huang, Pei Yu Wang, Ya Ju Hsieh, Kun Yi Chien, Yen Hsien Lee, Chia Chun Chang, Hsiang Yu Tang, Yu Tsun Lin, Chang Shung Tung, Ji Dung Luo, Ting-Wen Chen, Tzu Yang Lin, Mei Ling Cheng, Yi Ting Chen, Chau Ting Yeh, Ji Long Liu, Li Ying Sung, Ming Shi ShiaoJau Song Yu, Yu Sun Chang, Li Mei Pai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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. Metabolic enzymes form membraneless compartments to adapt to environmental changes. Lin et al. demonstrate that histidine catabolism coupled with the folate cycle contributes to methionine synthesis, which promotes protein methylation. This post-translational modification in turn induces CTPS filament formation to preserve CTPS but reduces its enzymatic activity under starvation.

Original languageEnglish
Pages (from-to)2733-2745.e7
JournalCell Reports
Issue number10
StatePublished - 4 Sep 2018


  • ATF4
  • CTP synthase
  • CTPS filament
  • MTHFD2
  • cancer
  • folate cycle
  • histidine
  • methylation
  • nutrient deprivation
  • one carbon

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