Zachara Lab


More than 3000 cytoplasmic,
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mitochondrial and nuclear proteins of metazoans are modified by O-linked beta-N-acetylglucosamine (O-GlcNAc). This dynamic post-translational modification is thought to regulate proteins in a manner analogous to protein phosphorylation. Deletion of the enzymes which add (OGT) and remove (O-GlcNAcase) is lethal, highlighting the importance of this simple sugar in regulating cellular homeostasis.

Right: O-GlcNAc is added and removed by just two enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA).


In
2004 we demonstrated that O-GlcNAcylation of intracellular proteins was a novel regulator of cell survival and a modulator of the cellular stress response. In response to diverse forms of cellular stress, the O-GlcNAc modification is increased on
covera
myriad proteins. Elevation of O-GlcNAc levels prior to or after the induction of injury promotes cell survival in models of heat stress, hypoxia, oxidative stress, ischemia repercussion injury, and trauma hemorrhage. Conversely, lowering O-GlcNAc levels sensitizes cells to various forms of injury. Together, these data suggest that modification of proteins by O-GlcNAc in an integral component of the cellular stress response.

Right: O-GlcNAc (green) is found on thousands of intracellular proteins, including nuclear pore proteins.


Elevation of O-GlcNAc levels modulates numerous pathways in a manner consistent with increased cell survival, including the expression of heat shock proteins.
HSPs
However, the molecular mechanisms by which O-GlcNAc promotes cell survival are unknown. Our laboratories goal is to understand the O-GlcNAc regulated stress response, how this can be manipulated to improve patient outcome, and how this response is misregulated in disease.

Right: Deletion of OGT affects the expression of 18 molecular chaperones, including HSP70