Regulation of the urea cycle by CPS1O-GlcNAcylation in response to dietary restriction and aging
Year: 2022
Type: article
Abstract: 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.
DOI: 10.1093/jmcb/mjac016
Institutions: Yale University, Xi'an Jiaotong University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,600
Awards: G1517811247, O-GlcNAc modification in metabolic homeostasis, An Ultra-Performance Liquid Chromatography System to Support Metabolomics at Yale University, G5855825020, G7229188214, 6500 QTrap Mass Spectrometer for Yale University, Regulation of hepatocyte response to chronic liver injury by subcellular calcium, Yale Liver Center
OpenAlex ID: W4220734260