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Regulation of the urea cycle by CPS1 O-GlcNAcylation in response to dietary restriction and aging
Jing Wu1,2 , Jiayu Liu1 , Kalina Lapenta1 , Reina Desrouleaux1 , Min-Dian Li1,* , Xiaoyong Yang1,*
1Department of Comparative Medicine, Department of Cellular and Molecular Physiology, and Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA
2School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China
*Correspondence to:Min-Dian Li , Xiaoyong Yang ,
J Mol Cell Biol, Volume 14, Issue 3, March 2022, mjac016,
Keyword: ageing, O-GlcNAcylation, urea cycle, carbamoyl phosphate synthetase 1, calorie restriction, posttranslational modification, dietary restriction

O-linked N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of intracellular proteins is a dynamic process broadly implicated in age-related disease, yet it remains uncharacterized whether and how O-GlcNAcylation contributes to the natural aging process. O-GlcNAc transferase (OGT) and the opposing enzyme O-GlcNAcase (OGA) control this nutrient-sensing protein modification in cells. Here, we show that global O-GlcNAc levels are increased in multiple tissues of aged mice. In aged liver, carbamoyl phosphate synthetase 1 (CPS1) is among the most heavily O-GlcNAcylated proteins. CPS1 O-GlcNAcylation is reversed by calorie restriction and is sensitive to genetic and pharmacological manipulations of the O-GlcNAc pathway. High glucose stimulates CPS1 O-GlcNAcylation and inhibits CPS1 activity. Liver-specific deletion of OGT potentiates CPS1 activity and renders CPS1 irresponsive to further stimulation by a prolonged fasting. Our results identify CPS1 O-GlcNAcylation as a key nutrient-sensing regulatory step in the urea cycle during aging and dietary restriction, implying a role for mitochondrial O-GlcNAcylation in nutritional regulation of longevity.