Demystifying the O-GlcNAc Code: A Systems View

Abstract

Post-translational modification with O-linked β-N-acetylglucosamine (O-GlcNAc), a process referred to as O-GlcNAcylation, occurs on a vast variety of proteins. Mounting evidence in the past several decades has clearly demonstrated that O-GlcNAcylation is a unique and ubiquitous modification. Reminiscent of a code, protein O-GlcNAcylation functions as a crucial regulator of nearly all cellular processes studied. The primary aim of this review is to summarize the developments in our understanding of myriad protein substrates modified by O-GlcNAcylation from a systems perspective. Specifically, we provide a comprehensive survey of O-GlcNAcylation in multiple species studied, including eukaryotes (e.g., protists, fungi, plants, Caenorhabditis elegans, Drosophila melanogaster, murine, and human), prokaryotes, and some viruses. We evaluate features (e.g., structural properties and sequence motifs) of O-GlcNAc modification on proteins across species. Given that O-GlcNAcylation functions in a species-, tissue-/cell-, protein-, and site-specific manner, we discuss the functional roles of O-GlcNAcylation on human proteins. We focus particularly on several classes of relatively well-characterized human proteins (including transcription factors, protein kinases, protein phosphatases, and E3 ubiquitin-ligases), with representative O-GlcNAc site-specific functions presented. We hope the systems view of the great endeavor in the past 35 years will help demystify the O-GlcNAc code and lead to more fascinating studies in the years to come.

Global O-GlcNAcylation changes impact desmin phosphorylation and its partition toward cytoskeleton in C2C12 skeletal muscle cells differentiated into myotubes

“…Furthermore, the interplay between phosphorylation and O-GlcNAcylation was firstly mentioned in 1987 66 ; since then, this interplay was extensively described on a large panel of proteins (for review, see 31 , 67 – 69 ). Interestingly, it was also described that O-GlcNAcylation modulates kinome and phosphatome 70 – 72 . In addition, it was shown that OGT and OGA interact with kinases and phosphatases within multienzymatic complexes permitting the phosphorylation and/or O-GlcNAcylation of proteins of interest 33 , 39 .…”

Nutrient-sensitive protein O-GlcNAcylation shapes daily biological rhythms

“…Many elegant reviews have summarized published functional investigations of O-GlcNAcylation on cellular proteins (e.g. [16,17,19,181,182]). To date, although circadian/daily rhythm of the O-GlcNAcome has yet to be conducted, our study showing robust daily rhythmicity in global protein O-GlcNAcylation in Drosophila tissues suggests that diverse cellular processes and molecular pathways could potentially be rhythmically regulated by daily cycling O-GlcNAcylation that is sensitive to metabolic input [15].…”

Penta-o-galloyl-beta-d-Glucose (PGG) inhibits inflammation in human rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis model

“…It includes phosphorylation, acetylation, glycosylation, ubiquitination, and hydroxylation (1)(2)(3). Phosphorylation and ubiquitination are extensively studied PTMs, however, it has become increasingly clear that numerous other covalent changes transpire to existing proteins (4)(5)(6). Among these important regulatory mechanisms, glycosylation, an addition of the single-sugar Nacetylglucosamine (O-GlcNAc) to serine or threonine on cytosolic and nuclear proteins are gaining significant relevance in various chronic and age-related diseases (7,8).…”