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The O-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress

View ORCID ProfileSarel J. Urso, View ORCID ProfileMarcella Comly, View ORCID ProfileJohn A. Hanover, Todd Lamitina
doi: https://doi.org/10.1101/2020.05.01.072033
Sarel J. Urso
1Graduate Program in Cell Biology and Molecular Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
4Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
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  • ORCID record for Sarel J. Urso
Marcella Comly
2Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD, 20892, USA
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John A. Hanover
2Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD, 20892, USA
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Todd Lamitina
1Graduate Program in Cell Biology and Molecular Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
3Division of Child Neurology, Department of Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA, 15224, USA
4Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
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  • For correspondence: stl52@pitt.edu
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Abstract

The conserved O-GlcNAc transferase OGT O-GlcNAcylates serine and threonine residues of intracellular proteins to regulate their function. OGT is required for viability in mammalian cells, but its specific roles in cellular physiology are poorly understood. Here we describe a conserved requirement for OGT in an essential aspect of cell physiology: the hypertonic stress response. Through a forward genetic screen in Caenorhabditis elegans, we discovered OGT is acutely required for osmoprotective protein expression and adaptation to hypertonic stress. Gene expression analysis shows that ogt-1 functions through a post-transcriptional mechanism. Human OGT partially rescues the C. elegans phenotypes, suggesting that the osmoregulatory functions of OGT are ancient. Intriguingly, mutations that ablate O-GlcNAcylation activity in either human or C. elegans OGT rescue the hypertonic stress response phenotype. Our findings are among the first to demonstrate a specific physiological role for OGT at the organismal level and demonstrate that OGT engages in important molecular functions outside of its well described roles in post-translational O-GlcNAcylation of intracellular proteins.

Author Summary The ability to sense and adapt to changes in the environment is an essential feature of cellular life. Changes in environmental salt and water concentrations can rapidly cause cell volume swelling or shrinkage and, if left unchecked, will lead to cell and organismal death. All organisms have developed similar physiological strategies for maintaining cell volume. However, the molecular mechanisms that control these physiological outputs are not well understood in animals. Using unbiased genetic screening in C. elegans, we discovered that a highly conserved enzyme called O-GlcNAc transferase (OGT) is essential for regulating physiological responses to increased environmental solute levels. A human form of OGT can functionally substitute for worm OGT, showing that this role is conserved across evolution. Surprisingly, the only known enzymatic activity of OGT was not required for this role, suggesting this enzyme has important undescribed molecular functions. Our studies reveal a new animal-specific role for OGT in the response to osmotic stress and show that C. elegans is an important model for defining the conserved molecular mechanisms that respond to alterations in cell volume.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 01, 2020.
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The O-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress
Sarel J. Urso, Marcella Comly, John A. Hanover, Todd Lamitina
bioRxiv 2020.05.01.072033; doi: https://doi.org/10.1101/2020.05.01.072033
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The O-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress
Sarel J. Urso, Marcella Comly, John A. Hanover, Todd Lamitina
bioRxiv 2020.05.01.072033; doi: https://doi.org/10.1101/2020.05.01.072033

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