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

doi:10.1016/j.celrep.2018.08.007

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:

Lin, Wei-Cheng ^[1]; Chakraborty, Archan ^[1]; Huang, Shih-Chia ^[2]; Wang, Pei-Yu ^[1]; Hsieh, Ya-Ju ^[1]; Chien, Kun-Yi ^[3]; Lee, Yen-Hsien ^[1]; Chang, Chia-Chun ^[4]; Tang, Hsiang-Yu ^[1]; Lin, Yu-Tsun ^[1];

^[5]; Luo, Ji-Dung ^[1]; Chen, Ting-Wen ^[3]; Lin, Tzu-Yang ^[6]; Cheng, Mei-Ling ^[3]; Chen, Yi-Ting ^[3]; Yeh, Chau-Ting ^[3]; Liu, Ji-Long ^[7]; Sung, Li-Ying ^[8]; Shiao, Ming-Shi ^[1] more »

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:: 2018-09-04

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.

Copy to clipboard


                    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.

Copy to clipboard


                    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.

Copy to clipboard


                    
@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}

}

Copy to clipboard

Journal Article:

Free Publicly Available Full Text

Accepted Manuscript (DOE)

Publisher's Version of Record

DOI: 10.1016/j.celrep.2018.08.007

Other availability

Search WorldCat to find libraries that may hold this journal

Citation Metrics:

Cited by: 4 works

Citation information provided by
Web of Science

Figures / Tables:

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 »

All figures and tables (7 total)

Save / Share:

Export Metadata

Save to My Library

Figures / Tables found in this record:

Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.

Similar records in OSTI.GOV collections:

Evolutionarily conserved IMPACT impairs various stress responses that require GCN1 for activating the eIF2 kinase GCN2

Journal Article Cambiaghi, Tavane D. ; Pereira, Catia M. ; Shanmugam, Renuka ; ... - Biochemical and Biophysical Research Communications

Highlights: •GCN1 is required for mammalian and yeast GCN2 function in a variety of conditions. •Mammalian IMPACT competes with GCN2 for GCN1 binding. •IMPACT and its yeast counterpart YIH1 downregulate GCN1-dependent GCN2 activation. -- Abstract: In response to a range of environmental stresses, phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2α) represses general protein synthesis coincident with increased translation of specific mRNAs, such as those encoding the transcription activators GCN4 and ATF4. The eIF2α kinase GCN2 is activated by amino acid starvation by a mechanism involving GCN2 binding to an activator protein GCN1, along with associationmore »« less
DOI: 10.1016/J.BBRC.2013.12.021
CTP synthase forms cytoophidia in the cytoplasm and nucleus

Journal Article Gou, Ke-Mian ; State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193 ; Chang, Chia-Chun ; ... - Experimental Cell Research

CTP synthase is an essential metabolic enzyme responsible for the de novo synthesis of CTP. Multiple studies have recently showed that CTP synthase protein molecules form filamentous structures termed cytoophidia or CTP synthase filaments in the cytoplasm of eukaryotic cells, as well as in bacteria. Here we report that CTP synthase can form cytoophidia not only in the cytoplasm, but also in the nucleus of eukaryotic cells. Both glutamine deprivation and glutamine analog treatment promote formation of cytoplasmic cytoophidia (C-cytoophidia) and nuclear cytoophidia (N-cytoophidia). N-cytoophidia are generally shorter and thinner than their cytoplasmic counterparts. In mammalian cells, both CTP synthasemore »« less
DOI: 10.1016/J.YEXCR.2014.01.029
Glutamine deprivation sensitizes human breast cancer MDA-MB-231 cells to TRIAL-mediated apoptosis

Journal Article Dilshara, Matharage Gayani ; Jeong, Jin-Woo ; Prasad Tharanga Jayasooriya, Rajapaksha Gedara ; ... - Biochemical and Biophysical Research Communications

Tumor cell metabolism is a promising target for various cancer treatments. Apart from aerobic glycolysis, cancer cell growth is dependent on glutamine (Gln) supply, leading to their survival and differentiation. Therefore, we examined whether treatment with TNF-related apoptosis-inducing ligand (TRAIL) sensitizes MDA-MB-231 cells to apoptosis under Gln deprivation condition (TRAIL/Gln deprivation). Gln deprivation decreased cell proliferation as expected, but did not induce remarkable cell death. TRAIL/Gln deprivation, however, significantly increased growth inhibition and morphological shrinkage of MDA-MB-231 cells compared to those induced by treatment with either Gln deprivation or TRAIL alone. Moreover, TRAIL/Gln deprivation upregulated the apoptotic sub-G{sub 1} phasemore »« less
DOI: 10.1016/J.BBRC.2017.02.059

Similar Records