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Title: 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:
 [1];  [1];  [2];  [1];  [1];  [3];  [1];  [4];  [1];  [1]; ORCiD logo [5];  [1];  [3];  [6];  [3];  [3];  [3];  [7];  [8];  [1] more »;  [3];  [1];  [3] « less
  1. Chang Gung University, Taoyuan (Taiwan)
  2. Genomics Research Center, Academia Sinica, Taipei (Taiwan)
  3. Chang Gung University, Taoyuan (Taiwan); Chang Gung Memorial Hospital, Linkou (Taiwan)
  4. National Taiwan University, Taipei (Taiwan)
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei (Taiwan); National Defense Medical Center, Taipei (Taiwan)
  7. Univ. of Oxford (United Kingdom); ShanghaiTech University (China)
  8. 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}
}

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Figures / Tables:

Figure 1 Figure 1: Histidine Is Required for CTPS Filament Formation Histidine Is Required for CTPS Filament Formation (A) HEp-2 cells were incubated with DMEM, serumnegative medium, Gln-negative medium, serum/ Gln-negative medium, and EBSS for 24 hr, followed by immunostaining against CTPS (green) and DAPI (blue). Scale bars: 10 $μ$m. (B) HEp-2more » cells were cultured in serum/Gln-negative medium and EBSS + EAA, with or without BCH (10 mM) treatment, for 24 hr. Cells were stained with anti-CTPS (green) and DAPI (blue). Scale bars, 10 $μ$m. (C) HEp-2 cells were incubated in the indicated concentrations of histidine in EBSS for the indicated times, followed by immunostaining against CTPS (green) and DAPI (blue). Scale bar: 10 $μ$m. (D) HEp-2 cells were incubated in serum/Glnnegative medium, with or without histidine (His + or His -) for 24 hr. HEp-2 cells were incubated in serum/Gln-negative medium for 16 hr, then added histidine (His addition) for 8 hr. Cells were stained with anti-CTPS (green) and DAPI (blue). Scale bars: 10 $μ$m. (E) HeLa and U2OS were incubated in serum/Glnnegative medium for 48 hr or EBSS + His for 24 hr, followed by immunostaining against CTP (green) and DAPI (blue). Scale bar: 10 $μ$m. The percentage of cells bearing CTPS filaments was calculated: mean ± SD, **p < 0.01 and ***p < 0.001.« less

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