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 in this work, 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. Finally, 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.
- Authors:
-
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- Chang Gung University, Taoyuan (Taiwan)
- Genomics Research Center, Academia Sinica, Taipei (Taiwan)
- Chang Gung University, Taoyuan (Taiwan); Chang Gung Memorial Hospital, Linkou (Taiwan)
- National Taiwan University, Taipei (Taiwan)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei (Taiwan); National Defense Medical Center, Taipei (Taiwan)
- Univ. of Oxford (United Kingdom); ShanghaiTech University (China)
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei (Taiwan); National Taiwan University, Taipei (Taiwan)
- Publication Date:
- Research Org.:
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE Laboratory Directed Research and Development (LDRD) Program
- OSTI Identifier:
- 1477654
- Report Number(s):
- LA-UR-17-30644
Journal ID: ISSN 2211-1247
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Cell Reports
- Additional Journal Information:
- Journal Volume: 24; Journal Issue: 10; Journal ID: ISSN 2211-1247
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biological Science
Citation Formats
Lin, Wei-Cheng, Chakraborty, Archan, Huang, Shih-Chia, Wang, Pei-Yu, Hsieh, Ya-Ju, Chien, Kun-Yi, Lee, Yen-Hsien, Chang, Chia-Chun, Tang, Hsiang-Yu, Lin, Yu-Tsun, Tung, Chang-Shung, Luo, Ji-Dung, Chen, Ting-Wen, Lin, Tzu-Yang, Cheng, Mei-Ling, Chen, Yi-Ting, Yeh, Chau-Ting, Liu, Ji-Long, Sung, Li-Ying, Shiao, Ming-Shi, Yu, Jau-Song, Chang, Yu-Sun, and Pai, Li-Mei. Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase. United States: N. p., 2018.
Web. doi:10.1016/j.celrep.2018.08.007.
Lin, Wei-Cheng, Chakraborty, Archan, Huang, Shih-Chia, Wang, Pei-Yu, Hsieh, Ya-Ju, Chien, Kun-Yi, Lee, Yen-Hsien, Chang, Chia-Chun, Tang, Hsiang-Yu, Lin, Yu-Tsun, Tung, Chang-Shung, Luo, Ji-Dung, Chen, Ting-Wen, Lin, Tzu-Yang, Cheng, Mei-Ling, Chen, Yi-Ting, Yeh, Chau-Ting, Liu, Ji-Long, Sung, Li-Ying, Shiao, Ming-Shi, Yu, Jau-Song, Chang, Yu-Sun, & Pai, Li-Mei. Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase. United States. doi:10.1016/j.celrep.2018.08.007.
Lin, Wei-Cheng, Chakraborty, Archan, Huang, Shih-Chia, Wang, Pei-Yu, Hsieh, Ya-Ju, Chien, Kun-Yi, Lee, Yen-Hsien, Chang, Chia-Chun, Tang, Hsiang-Yu, Lin, Yu-Tsun, Tung, Chang-Shung, Luo, Ji-Dung, Chen, Ting-Wen, Lin, Tzu-Yang, Cheng, Mei-Ling, Chen, Yi-Ting, Yeh, Chau-Ting, Liu, Ji-Long, Sung, Li-Ying, Shiao, Ming-Shi, Yu, Jau-Song, Chang, Yu-Sun, and Pai, Li-Mei. Tue .
"Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase". United States. doi:10.1016/j.celrep.2018.08.007. https://www.osti.gov/servlets/purl/1477654.
@article{osti_1477654,
title = {Histidine-Dependent Protein Methylation Is Required for Compartmentalization of CTP Synthase},
author = {Lin, Wei-Cheng and Chakraborty, Archan and Huang, Shih-Chia and Wang, Pei-Yu and Hsieh, Ya-Ju and Chien, Kun-Yi and Lee, Yen-Hsien and Chang, Chia-Chun and Tang, Hsiang-Yu and Lin, Yu-Tsun and Tung, Chang-Shung and Luo, Ji-Dung and Chen, Ting-Wen and Lin, Tzu-Yang and Cheng, Mei-Ling and Chen, Yi-Ting and Yeh, Chau-Ting and Liu, Ji-Long and Sung, Li-Ying and Shiao, Ming-Shi and Yu, Jau-Song and Chang, Yu-Sun and Pai, Li-Mei},
abstractNote = {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 in this work, 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. Finally, 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.},
doi = {10.1016/j.celrep.2018.08.007},
journal = {Cell Reports},
number = 10,
volume = 24,
place = {United States},
year = {2018},
month = {9}
}
Web of Science
Figures / Tables:

Works referencing / citing this record:
Forming cytoophidia prolongs the half-life of CTP synthase
journal, June 2019
- Sun, Zhe; Liu, Ji-Long
- Cell Discovery, Vol. 5, Issue 1
Down‐regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle‐related genes
journal, November 2019
- Yu, Chang; Yang, Lehe; Cai, Mengsi
- Journal of Cellular and Molecular Medicine, Vol. 24, Issue 2
Filamentation of asparagine synthetase in Saccharomyces cerevisiae
journal, October 2018
- Zhang, Shanshan; Ding, Kang; Shen, Qing-Ji
- PLOS Genetics, Vol. 14, Issue 10
Figures / Tables found in this record: