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

Authors :
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 Shiao
Jau-Song Yu
Yu-Sun Chang
Li-Mei Pai
Source :
Cell Reports, Vol 24, Iss 10, Pp 2733-2745.e7 (2018)
Publication Year :
2018
Publisher :
Elsevier, 2018.

Abstract

Summary: 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. Keywords: histidine, CTP synthase, CTPS filament, ATF4, MTHFD2, folate cycle, one carbon, methylation, nutrient deprivation, cancer

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
22111247
Volume :
24
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.72595cfbc69e420ab2bc36c8b4f98595
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2018.08.007