Dr. Zachara and her team are engaged in understanding which proteins are modified dynamically by O-GlcNAc in response to stress, and how this alters protein function in such a way that elevating O-GlcNAc before, or immediately after, cellular injury is protective in both in vitro and in vivo models.
In response to multiple forms of cellular stress, levels of the O-linked β-N-acetylglucosamine (O-GlcNAc) protein modification are elevated rapidly and dynamically on myriad nuclear, mitocohdrial and cytoplasmic proteins. Several studies demonstrate that elevation of O-GlcNAc prior to heat stress, oxidative stress, hypoxia, trauma hemorrhage and ischemia reperfusion injury is protective, suggesting that increased O-GlcNAc in response to stress is a survival response of cells injury. However, the mechanisms by which O-GlcNAc regulates protein function leading to cell survival have not been defined.
Dr. Zachara's long-term goal is to determine how stress-induced changes in the O-GlcNAc protein modification lead to increased cell/tissue survival in response to injury, in order to develop novel strategies for the treatment of numerous diseases, including ischemia reperfusion injury.
Lab Website: Zachara Lab
Martinez M, Renuse S, Kreimer S, O'Meally R, Natov P, Madugundu AK, Nirujogi RS, Tahir R, Cole R, Pandey A, Zachara NE. Quantitative Proteomics Reveals that the OGT Interactome is Remodeled in Response to Oxidative Stress. Mol Cell Proteomics. 2021 Mar 11:100069. doi: 10.1016/j.mcpro.2021.100069. Epub ahead of print. PMID: 33716169
Taparra K, Wang H, Malek R, Lafargue A, Barbhuiya MA, Wang X, Simons BW, Ballew M, Nugent K, Groves J, Williams RD, Shiraishi T, Verdone J, Yildirir G, Henry R, Zhang B, Wong J, Wang KK, Nelkin BD, Pienta KJ, Felsher D, Zachara NE, Tran PT. O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis. J Clin Invest. 2018 Nov 1;128(11):4924-4937. doi: 10.1172/JCI94844. Epub 2018 Sep 24. PMID: 30130254; PMCID: PMC6205381
Groves JA, Maduka AO, O'Meally RN, Cole RN, Zachara NE. Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress. J Biol Chem. 2017 Apr 21;292(16):6493-6511. doi: 10.1074/jbc.M116.760785. Epub 2017 Feb 23. PMID: 28232487; PMCID: PMC5399103
Lee A, Miller D, Henry R, Paruchuri VD, O'Meally RN, Boronina T, Cole RN, Zachara NE. Combined Antibody/Lectin Enrichment Identifies Extensive Changes in the O-GlcNAc Sub-proteome upon Oxidative Stress. J Proteome Res. 2016 Dec 2;15(12):4318-4336. doi: 10.1021/acs.jproteome.6b00369. Epub 2016 Oct 14. PMID: 27669760
Kazemi Z., Chang H., Haserodt S. K., McKen C., Zachara N.E. (2010) O-GlcNAc Regulates Stress-Induced Heat Shock Protein Expression in a GSK-3 Dependent Manner. J. Biol. Chem., 285, 39096-39107