摘要
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 heavilyO-GlcNAcylated proteins.CPS1O-GlcNAcylation is reversed by calorie restriction and is sensitive to genetic and pharmacological manipulations of theO-GlcNAc pathway.High glucose stimulates CPS1O-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.
基金
was supported by grants from National Institutes of Health(R01DK089098 and P01DK57751)
American Diabetes Association(1-19-IBS-119)
X.Y.and a Glenn/AFAR Scholarship for Research in the Biology of Aging to M.-D.L
Yale School of Medicine and by the Office of The Director,National Institutes of Health(S10OD02365101A1,S10OD019967,and S10OD018034).
