Over the past 35 years, ~1700 articles have characterized protein O-GlcNAcylation. Found in almost all living organisms, this post-translational modification of serine and threonine residues is highly conserved and key to biological processes. With half of the primary research articles using human models, the O-GlcNAcome recently reached a milestone of 5000 human proteins identified. Herein, we provide an extensive inventory of human O-GlcNAcylated proteins, their O-GlcNAc sites, identification methods, and corresponding references (www.oglcnac.mcw.edu). In the absence of a comprehensive online resource for O-GlcNAcylated proteins, this list serves as the only database of O-GlcNAcylated proteins. Based on the thorough analysis of the amino acid sequence surrounding 7002 O-GlcNAc sites, we progress toward a more robust semi-consensus sequence for O-GlcNAcylation. Moreover, we offer a comprehensive meta-analysis of human O-GlcNAcylated proteins for protein domains, cellular and tissue distribution, and pathways in health and diseases, reinforcing that O-GlcNAcylation is a master regulator of cell signaling, equal to the widely studied phosphorylation.

Nutrient-driven -GlcNAcylation is strikingly abundant in the brain and has been linked to development and neurodegenerative disease. We selectively targeted the-GlcNAcase () gene in the mouse brain to define the role of -GlcNAc cycling in the central nervous system. Brain knockout animals exhibited dramatically increased brain-GlcNAc levels and pleiotropic phenotypes, including early-onset obesity, growth defects, and metabolic dysregulation. Anatomical defects in the knockout included delayed brain differentiation and neurogenesis as well as abnormal proliferation accompanying a developmental delay. The molecular basis for these defects included transcriptional changes accompanying differentiating embryonic stem cells. In KO mouse ES cells, we observed pronounced changes in expression of pluripotency markers, including Sox2, Nanog, and Otx2. These findings link the -GlcNAc modification to mammalian neurogenesis and highlight the role of this nutrient-sensing pathway in developmental plasticity and metabolic homeostasis.

Non-nutritive sweeteners (NNS) are marketed as sugar alternatives providing sweet taste with few or no calories. Yet their consumption has been linked to metabolic dysfunction and changes in the gut microbiome. NNS exposure mostly originates from diet beverages and sweetener packages in adults or breastmilk in infants. Consequences of early life exposure remain largely unknown. We exposed pregnant and lactating mice to NNS (sucralose, acesulfame-K) at doses relevant for human consumption. While the pups’ exposure was low, metabolic changes were drastic, indicating extensive downregulation of hepatic detoxification mechanisms and changes in bacterial metabolites. Microbiome profiling confirmed a significant increase in firmicutes and a striking decrease of Akkermansia muciniphila . Similar microbiome alterations in humans have been linked to metabolic disease and obesity. While our findings need to be reproduced in humans, they suggest that NNS consumption during pregnancy and lactation may have adverse effects on infant metabolism.