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O-GlcNAc, A Novel Regulator of the Cellular Stress Response and Cell Surival
The dynamic modification of intracellular proteins by monosaccharides of O-linked N-acetylglucosamine (O-GlcNAc) plays key roles in cellular physiology and disease progression. Underpinning this observation are some 3000 O-GlcNAc-modified proteins that regulate cellular pathways such as epigenetics, gene expression, translation, protein degradation, signal transduction, mitochondrial bioenergetics, the cell cycle and protein localization. In 2004, we reported that global O-GlcNAc levels were induced in a dose-dependent manner in response to a wide range of cellular stressors in several mammalian cell lines and that augmentation of O-GlcNAc levels promoted the induction of HSPs and cell survival in a model of heat stress. Combined, these data suggested that stress-induced O-GlcNAcylation was one target of the mammalian stress response. Since then, numerous reports have demonstrated that this response, termed the O-GlcNAc-mediated stress response, is conserved in both transformed and primary cells as well as several forms of physiological injury. Furthermore, we and others have demonstrated that augmentation of O-GlcNAcylation promotes cell and tissue survival in models ranging from heat stress to myocardial ischemia reperfusion (I/R) injury (Heart attack). .
Broadly, our goal is to understand the O-GlcNAc-mediated stress response in order to identify new therapeutic targets that enhance stress-tolerance and promote survival in models such as I/R injury, and to determine how dysregulation of the O-GlcNAc-mediated stress response contributes to pathologies such as type II diabetes and aging. Current studies in the laboratory include developing analytical and genetic tools for studying O-GlcNAcylation in vitro and in vivo, defining the dynamic O-GlcNAc sub-proteome of the ischemia heart, elucidating the role of O-GlcNAc in the regulation of autophagy, determining how cancer cells have hijacked the O-GlcNAc-mediated stress response, and identifying key regulators of the enzymes that cycle O-GlcNAc. Such studies utilize a broad range of techniques, from mouse genetics to high-end proteomics.
Groves JA, Maduka AO, O’Meally RN, Cole RN, and Zachara NE.. Fatty acid synthase: a novel oxidative stress-induced interactor and inhibitor of the O-GlcNAcase. In Press, JBC.
Martinez M, Dias T, Natov P, and Zachara NE. Stress-Induced O-GlcNAcylation, an Adaptive Process of Injured Cells. Biochemical Society Transactions, 2017 45(1):237-249.
Lee A, Henry R, Miller D, Paruchuri VDP, O’Meally R, Boronina T, Cole RN, Zachara NE. Combined Antibody/Lectin-Enrichment Identifies Extensive Changes in the O-GlcNAc Subproteome Upon Oxidative Stress, Journal of Proteome Research; 15(12):4318-4336.
Hou CW, Mohanan V, Zachara NE, Grimes CL. Identification and biological consequences of the O-GlcNAc modification of the human innate immune receptor, Nod2. Glycobiology 2016;26(1):13-8.
Fahie K, and Zachara N. Molecular Functions of Glycoconjugates in Autophagy, Journal of Molecular Biology, 2016 428(16):3305-24.
Taparra K, Tran P, and Zachara NE. Hijacking the Hexosamine Biosynthetic Pathway to Promote EMT-Mediated Neoplastic Phenotypes. Frontiers in Oncology, 2016, 6:85
Zhu Y, Liu T, Madden Z, Yuzwa SA, Murray K, Cecioni S, Zachara NE, and Vocadlo DJ. Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter. Journal of Molecular Cell 2015 8(1):2-16.
Zhong J, Martinez M, Sengupta S, Lee A, Wu X, Chaerkady R, O'Meally R, Cole RN, Pandey A, Zachara NE Quantitative Phosphoproteomics Reveals Crosstalk Between Phosphorylation and O-GlcNAc in the DNA Damage Response Pathway. Proteomics 2015;15(2-3):591-607.
Reeves R, Lee A, Henry R, and Zachara NE. Characterization of the Specificity of O-GlcNAc Reactive Antibodies Under Conditions of Starvation and Stress. Analytical Biochemistry 2014;457:8-18.
Tardio L*, Andrés-Bergós J*, Zachara NE, Larrañaga-Vera A, Rodriguez-Villar C, Herrero-Beaumont G, Largo R. O-linked N-Acetylglucosamine (O-GlcNAc) protein modification is increased in the cartilage of patients with knee osteoarthritis. Osteoarthritis Cartilage 2014; 22(2):259-63. * Denotes co-first authors.
Jensen RV, Johnsen J, Kristiansen SB, Zachara NE, and Botker HE. Ischemic Preconditioning Increases Myocardial O-GlcNAc Glycosylation. Scandinavian Cardiovascular Journal 2013;47(3):168-74.
Groves J, Lee A, Yildirir G, and Zachara NE. Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis. Cell Stress and Chaperones 2013;18(5):535-58.
Jensen RV, Zachara NE, Nielsen PH, Kimose HH, Kristiansen SB, and Botker HE. Impact of O-GlcNAc on cardioprotection by remote ischemic preconditioning in non-diabetic and diabetic patients. Cardiovascular Research 2013; 97(2):369-378/p
Tarrant MK, Rho H, Xie Z, Blackshaw S, Jiang Y, Gross C, Qian J, Ichikawa Y, Zachara N, Etzkorn F, Hart GW, Jeong J, Zhu H, Cole PA.. Multi-faceted Regulation of Protein Kinase CK2 by Phosphorylation and Glycosylation Revealed through Semisynthesis. Nature Chemical Biology 2012;8(3):262-269.
Zachara NE, Molina H, Wong K, Pandey A, Hart GW. The dynamic stress-induced O-GlcNAcome highlights functions for O-GlcNAc in DNA Repair and other cellular pathways. Amino Acids 2011;40(3):793-808.
Zachara NE. The Roles of O-Linked N-Acetylglucosamine (O-GlcNAc) in Cardiac Physiology and Disease. American J Physiol Heart Circ Physiol. 2012: 302(10): H1905-H1918
Paruchuri V.D.P. and Zachara NE. Defining the Cardiac O-GlcNAcome, A Review of Approaches and Methadologies”, Special series: Integrating proteomics into cardiovascular disease in Circulation: Cardiovascular Genetics 2011 4(6):710-718.