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

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

doi:10.1016/j.celrep.2018.08.007

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

Cell Rep. 2018 Sep 4;24(10):2733-2745.e7. doi: 10.1016/j.celrep.2018.08.007.

Authors

Wei-Cheng Lin¹, Archan Chakraborty², Shih-Chia Huang³, Pei-Yu Wang¹, Ya-Ju Hsieh⁴, Kun-Yi Chien⁵, Yen-Hsien Lee⁶, Chia-Chun Chang⁷, Hsiang-Yu Tang⁸, Yu-Tsun Lin⁶, Chang-Shung Tung⁹, Ji-Dung Luo¹⁰, Ting-Wen Chen¹¹, Tzu-Yang Lin¹², Mei-Ling Cheng¹³, Yi-Ting Chen¹⁴, Chau-Ting Yeh¹⁵, Ji-Long Liu¹⁶, Li-Ying Sung¹⁷, Ming-Shi Shiao¹⁸, Jau-Song Yu¹⁹, Yu-Sun Chang²⁰, Li-Mei Pai²¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan.
² Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
³ Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
⁴ Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan.
⁵ Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Clinical Proteomics Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan.
⁶ Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
⁷ Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
⁸ Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan 33302, Taiwan.
⁹ Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
¹⁰ Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Bioinformatics Core Laboratory, Chang Gung University, Taoyuan 33302, Taiwan.
¹¹ Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Departments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹² Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan.
¹³ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹⁴ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹⁵ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.
¹⁶ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
¹⁷ Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan; Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
¹⁸ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan 33302, Taiwan.
¹⁹ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.
²⁰ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan.
²¹ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan 33302, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan. Electronic address: pai@mail.cgu.edu.tw.

PMID: 30184506
DOI: 10.1016/j.celrep.2018.08.007

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, 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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbon-Nitrogen Ligases / chemistry
Carbon-Nitrogen Ligases / genetics
Carbon-Nitrogen Ligases / metabolism*
Folic Acid / metabolism
Histidine / metabolism*
Homocysteine / metabolism
Humans
Methylation
Protein Processing, Post-Translational
Protein Serine-Threonine Kinases / metabolism

Substances

Homocysteine
Histidine
Folic Acid
Protein Serine-Threonine Kinases
Carbon-Nitrogen Ligases
CTP synthetase

Abstract

Publication types

MeSH terms

Substances

Grants and funding