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

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

doi:10.1016/j.celrep.2018.08.007

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

Journal Article · 04 September 2018 · Cell Reports

DOI: https://doi.org/10.1016/j.celrep.2018.08.007 · OSTI ID:1477654

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)

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.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1477654

Report Number(s):: LA-UR-17-30644

Journal Information:: Cell Reports, Vol. 24, Issue 10; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 26 works

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