2. Academic Validation
  3. CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis

CLOCK Acetylates ASS1 to Drive Circadian Rhythm of Ureagenesis

  • Mol Cell. 2017 Oct 5;68(1):198-209.e6. doi: 10.1016/j.molcel.2017.09.008.
Ran Lin 1,  Yan Mo 2,  Haihong Zha 3,  Zhipeng Qu 4,  Pancheng Xie 4,  Zheng-Jiang Zhu 3,  Ying Xu 4,  Yue Xiong 5,  Kun-Liang Guan 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. Electronic address: rlin@fudan.edu.cn.
  • 2 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 4 Cam-Su Genomic Resource Center, Soochow University, Suzhou 215123, China.
  • 5 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: yxiong@email.unc.edu.
  • 6 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China; Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
PMID: 28985504 DOI: 10.1016/j.molcel.2017.09.008
Abstract

In addition to responding to environmental entrainment with diurnal variation, metabolism is also tightly controlled by cell-autonomous circadian clock. Extensive studies have revealed key roles of transcription in circadian control. Post-transcriptional regulation for the rhythmic gating of metabolic Enzymes remains elusive. Here, we show that arginine biosynthesis and subsequent ureagenesis are collectively regulated by CLOCK (circadian locomotor output cycles kaput) in circadian rhythms. Facilitated by BMAL1 (brain and muscle Arnt-like protein), CLOCK directly acetylates K165 and K176 of argininosuccinate synthase (ASS1) to inactivate ASS1, which catalyzes the rate-limiting step of arginine biosynthesis. ASS1 acetylation by CLOCK exhibits circadian oscillation in human cells and mouse liver, possibly caused by rhythmic interaction between CLOCK and ASS1, leading to the circadian regulation of ASS1 and ureagenesis. Furthermore, we also identified NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 (NDUFA9) and inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as acetylation substrates of CLOCK. Taken together, CLOCK modulates metabolic rhythmicity by acting as a rhythmic acetyl-transferase for metabolic Enzymes.

Keywords

acetylation; circadian; metabolism; ureagenesis.

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