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

Abstract
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.
AuthorsWei-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 Shiao, Jau-Song Yu, Yu-Sun Chang, Li-Mei Pai
JournalCell reports (Cell Rep) Vol. 24 Issue 10 Pg. 2733-2745.e7 (09 04 2018) ISSN: 2211-1247 [Electronic] United States
PMID30184506 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Homocysteine
  • Histidine
  • Folic Acid
  • Protein Serine-Threonine Kinases
  • Carbon-Nitrogen Ligases
  • CTP synthetase
Topics
  • Animals
  • Carbon-Nitrogen Ligases (chemistry, genetics, metabolism)
  • Folic Acid (metabolism)
  • Histidine (metabolism)
  • Homocysteine (metabolism)
  • Humans
  • Methylation
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases (metabolism)

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