O-GlcNAcylation: A major nutrient/stress sensor that regulates cellular physiology

O-GlcNAcylation of nuclear, cytoplasmic, and mitochondrial proteins was discovered over four decades ago (1Torres C.R. Hart G.W. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc.The Journal of biological chemistry. 1984; 259: 3308-3317Abstract Full Text PDF PubMed Google Scholar,2Holt G.D. Hart G.W. The subcellular distribution of terminal N-acetylglucosamine moieties. Localization of a novel protein-saccharide linkage, O-linked GlcNAc.The Journal of biological chemistry. 1986; 261: 8049-8057Abstract Full Text PDF PubMed Google Scholar). Work from many laboratories has shown that the cycling of O-linked N-acetylglucosamine (O-GlcNAc) on proteins serves as an essential nutrient/stress sensor to regulate transcription, signaling, DNA methylation and repair, translation, protein trafficking, and cell division in response to glucose and other nutrients (for review, (3Hart G.W. Nutrient Regulation of Signaling & Transcription.The Journal of biological chemistry. 2019; 294: 2211-2231Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)). Global O-GlcNAcylation is also increased in most forms of cellular stress (4Zachara N.E. Hart G.W. O-GlcNAc a sensor of cellular state: the role of nucleocytoplasmic glycosylation in modulating cellular function in response to nutrition and stress.Biochimica et biophysica acta. 2004; 1673: 13-28Crossref PubMed Scopus (0) Google Scholar). Currently, there are known to be at-least eight thousand human proteins modified and regulated by this dynamic sugar modification of proteins (5Wulff-Fuentes E. Berendt R.R. Massman L. Danner L. Malard F. Vora J. Kahsay R. Olivier-Van Stichelen S. The human O-GlcNAcome database and meta-analysis.Sci Data. 2021; 8: 25Crossref PubMed Scopus (133) Google Scholar). O-GlcNAcylation has extensive crosstalk with phosphorylation both at the site level on polypeptides, and by modifying many kinases. O-GlcNAcylation also cross talks to regulate ubiquitination, methylation, acetylation, and other post-translational modifications. The molecular functions of O-GlcNAc depend not only on the protein that is modified but also on the site on the polypeptide to which it is attached. Due to O-GlcNAc’s critical role in regulating nearly every cellular process, it is not surprising that it plays a direct role in the etiology of metabolic diseases associated with aging, including diabetes, cardiovascular disease, cancer, and neurodegeneration (6Banerjee P.S. Lagerlof O. Hart G.W. Roles of O-GlcNAc in chronic diseases of aging.Molecular aspects of medicine. 2016; 51: 1-15Crossref PubMed Scopus (0) Google Scholar,7Bond M.R. Hanover J.A. O-GlcNAc cycling: a link between metabolism and chronic disease.Annual review of nutrition. 2013; 33: 205-229Crossref PubMed Scopus (98) Google Scholar) (Figure 1). In this Thematic Series, we have selected topics that first illustrate the state of our knowledge about the roles of O-GlcNAcylation in fundamental cellular processes, such as signaling, transcription, DNA repair, circadian clocks, and in the regulation of cell division, and follow with five reviews on O-GlcNAc’s roles in various human diseases. Nelson et al. (8Nelson Z.M. Leonard G.D. Fehl C. Tools for investigating O-GlcNAc in signaling and other fundamental biological pathways.The Journal of biological chemistry. 2024; 300105615Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar) present an overview on how O-GlcNAcylation regulates key signaling pathways, including G-protein coupled receptors, growth factors, mitogen activated protein kinase pathways, lipid sensing and cytokine signaling pathways. They also summarize methodological and chemical biology advances that have allowed the elucidation of O-GlcNAc’s roles in these signaling pathways. Brian Lewis (9Lewis B.A. The role of O-GlcNAcylation in RNA polymerase II transcription.The Journal of biological chemistry. 2024; 300105705Abstract Full Text Full Text PDF Scopus (0) Google Scholar) summarizes the evidence that O-GlcNAcylation of RNA polymerase II and basal transcription factors, plays critical roles in initiation, pausing and elongation during the transcription cycle. Wu et al. (10Wu C. Li J. Lu L. Li M. Yuan Y. Li J. OGT and OGA: Sweet guardians of the genome.The Journal of biological chemistry. 2024; 300107141Abstract Full Text Full Text PDF Scopus (0) Google Scholar) review mechanisms by which O-GlcNAcylation regulates various DNA damage response pathways including, homologous recombination, non-homologous end joining, base excision repair and translesion DNA synthesis. Liu et al. (11Liu X. Cai Y.D. Chiu J.C. Regulation of protein O-GlcNAcylation by circadian, metabolic, and cellular signals.The Journal of biological chemistry. 2024; 300105616Abstract Full Text Full Text PDF Scopus (2) Google Scholar) discuss the roles of O-GlcNAcylation in the modulation of circadian rhythms by the timing of food intake and conversely how O-GlcNAcylation is regulated by circadian clocks independent of food consumption time. They further propose that O-GlcNAcylation is a generalized cellular status effector that responds to cellular signals and conditions, such as endoplasmic reticulum stress, apoptosis, and infection. Zhang and Wang (12Zhang J. Wang Y. Emerging roles of O-GlcNAcylation in protein trafficking and secretion.The Journal of biological chemistry. 2024; 300105677Abstract Full Text Full Text PDF Scopus (1) Google Scholar) describe how O-GlcNAcylation of key proteins involved in protein trafficking within cells, such as coat protein complexes (COPI and COPII), clathrin, SNARES, and GRASP55, regulate vesicle budding and fusion in both anterograde and retrograde trafficking. Saunders et al. (13Saunders H. Dias W.B. Slawson C. Growing and dividing: how O-GlcNAcylation leads the way.The Journal of biological chemistry. 2023; 299105330Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar) review the body of evidence that O-GlcNAcylation regulates cellular progression through the cell cycle. They highlight O-GlcNAc’s roles in regulating the G1 phase of the cell cycle, its control of DNA replication and repair, and its organization of mitotic progression and spindle dynamics. The final five reviews in this Thematic Series describe the myriad roles that O-GlcNAcylation plays in the etiologies of genetic diseases of development, and chronic diseases associated with aging (Figure 1). Mayfield et al. (14Mayfield J.M. Hitefield N.L. Czajewski I. Vanhye L. Holden L. Morvava E. van Aalten D.M.F. Wells L. O-GlcNAc transferase congential disorder of glycosylation: Potential mechanistic targets revealed by evaluating the OGT interactome.The Journal of biological chemistry. 2024; 300107599Google Scholar) describe our current knowledge on an O-GlcNAc transferase (OGT) congenital disorder of glycosylation (OGT-CDG) that results in X-linked intellectual disability that was first biochemically characterized in 2017 (15Vaidyanathan K. Niranjan T. Selvan N. Teo C.F. May M. Patel S. Weatherly B. Skinner C. Opitz J. Carey J. Viskochil D. Gecz J. Shaw M. Peng Y. Alexov E. Wang T. Schwartz C. Wells L. Identification and characterization of a missense mutation in the O-linked beta-N-acetylglucosamine (O-GlcNAc) trasferase gene that segregates with X-linked intellectual disability.The Journal of biological chemistry. 2017; 292: 8948Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). They propose that different variants in OGT may disrupt the enzyme’s interactome and contribute to the heterogeneous neural specific phenotypes of OGT-CDGs and dysregulation of neuronal development. Umapathi et al. (16Umapathi P. Aggarwal A. Zahra F. Narayanan B. Zachara N.E. The multifaceted role of intracellular glycosylation in cytoprotection and heart disease.The Journal of biological chemistry. 2024; 300107296Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar) describe the paradoxical roles that O-GlcNAcylation plays in the heart. Short-term elevated O-GlcNAcylation protects the heart from environmental stresses such as heat shock, hypoxia/reoxygenation injury and sepsis by preventing apoptosis and necrosis. In contrast, prolonged elevation or reduction in O-GlcNAcylation produces a maladaptive response associated with cardiac pathologies, such as hypertrophy and heart failure. Ramakrishnan (17Ramakrishnan P. O-GlcNAcylation and immune cell signaling: A review of known and a preview of unknown.The Journal of biological chemistry. 2024; 107349Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) summarizes the critical roles O-GlcNAcylation plays in regulation of physiological and pathological aspects of cellular immune functions. In particular, he also enumerates major remaining questions in our understanding the molecular processes as to how nutrients regulate immunity. Minh et al. (18Le Minh G. Esquea E.M. Young R.G. Huang J. Reginato M.J. On a sugar high: Role of O-GlcNAcylation in cancer.The Journal of biological chemistry. 2023; 299105344Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar) describe how O-GlcNAcylation is increased in nearly all types of cancer, and how O-GlcNAcylation plays a critical role in regulating many cellular processes that are hallmarks of cancer. Pratt and Vocadlo (19Pratt M.R. Vocadlo D.J. Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases.The Journal of biological chemistry. 2023; 299105411Abstract Full Text Full Text PDF Scopus (3) Google Scholar) describe the development of potent and highly specific inhibitors of O-GlcNAcase (OGA), and their potential uses as drugs to treat Alzheimer’s and Parkinson’s disease. They also illustrate how these OGA inhibitors and the development of chemical methods to stoichiometrically O-GlcNAcylate proteins have clarified the effects of O-GlcNAc on protein aggregation and in regulating heat shock proteins. At the time of its discovery over forty years ago, it was dogma that protein glycosylation did not occur in the nucleus and cytoplasm. However, we now know that O-GlcNAcylation is not only the most dynamic form of protein glycosylation that serves as a major nutrient/stress sensor to regulate nearly every cellular process, but also that dysregulation of O-GlcNAcylation underlies many of the etiologies of major chronic diseases associated with aging (Figure 1). This special issue illustrates some of the best examples of O-GlcNAc’s myriad roles in cellular physiology and in human disease. Hopefully, these reviews will inspire future research into this rapidly developing field. The authors’ original research was supported in part by NIH P01HL107153, R01GM116891, R01DK124366, R21HD097562, R01HD110099 and the Georgia Research Alliance.