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O-GlcNAc transferase plays a non-catalytic role in C. elegans male fertility

Daniel Konzman, Tetsunari Fukushige, Mesgana Dagnachew, Michael Krause, View ORCID ProfileJohn A. Hanover
doi: https://doi.org/10.1101/2022.05.26.493566
Daniel Konzman
1Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
2Johns Hopkins University Department of Biology, 3400 N. Charles Street, Baltimore, MD, 21218, USA
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Tetsunari Fukushige
3Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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Mesgana Dagnachew
1Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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Michael Krause
3Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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John A. Hanover
1Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
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  • ORCID record for John A. Hanover
  • For correspondence: johnh@bdg8.niddk.nih.gov
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Abstract

Animal behavior is influenced by the competing drives to maintain energy and to reproduce. The balance between these evolutionary pressures and how nutrient signaling pathways intersect with mating drive remains unclear. The nutrient sensor O-GlcNAc transferase, which post-translationally modifies intracellular proteins with a single monosaccharide, is responsive to cellular nutrient status and regulates diverse biological processes. Though essential in most metazoans, O-GlcNAc transferase (ogt-1) is dispensable in Caenorhabditis elegans, allowing genetic analysis of its physiological roles. Compared to control, ogt-1 males have a four-fold reduction in mean offspring, with nearly two thirds producing zero progeny. Interestingly, we found that isolated ogt-1 males are less likely to engage in mate-searching, and they initiate mating less often when exposed to mates. In addition, ogt-1 males which do initiate mating are less likely to continue with subsequent steps in the mating process, resulting in fewer successful sperm transfers. Lowering barriers to mating such as immobilizing mates or allowing more mating time significantly improves ogt-1 male mating. Surprisingly, we found high fertility levels for ogt-1 mutant males with hypodermal expression of wild-type ogt-1 and by ogt-1 harboring mutations that prevent the transfer of O-GlcNAc by OGT-1. This suggests OGT-1 serves a non-catalytic function in the hypodermis impacting the male mating drive. This study builds upon research on the nutrient sensor O- GlcNAc transferase and demonstrates a role it plays in the interplay between the evolutionary drives for reproduction and survival.

Author Summary Animals must make decisions on whether to engage in reproduction or conserve energy. These decisions must take into account the energy available to the animal, therefore making the nutrient sensing enzyme OGT of particular interest. In response to nutrient levels in the cell, OGT transfers the GlcNAc sugar onto proteins to regulate their function. OGT is implicated in a number of human diseases including diabetes, cancer, and X-linked intellectual disability. By deleting the gene encoding OGT in the nematode C. elegans, we show OGT is required for male fertility. We assessed the behavior of these mutant male worms and found they have a reduced mating drive. Surprisingly, restoring OGT specifically in the hypodermis was able to raise male fertility and mating drive back to normal levels. In addition, missense mutations in the OGT catalytic domain which prevent the enzyme from transferring GlcNAc do not negatively impact fertility, suggesting a different function of OGT is important in this process. Our study demonstrates that OGT is important in critical behavioral decisions and that further investigation in C. elegans may help reveal new functions of the enzyme.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted May 26, 2022.
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O-GlcNAc transferase plays a non-catalytic role in C. elegans male fertility
Daniel Konzman, Tetsunari Fukushige, Mesgana Dagnachew, Michael Krause, John A. Hanover
bioRxiv 2022.05.26.493566; doi: https://doi.org/10.1101/2022.05.26.493566
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O-GlcNAc transferase plays a non-catalytic role in C. elegans male fertility
Daniel Konzman, Tetsunari Fukushige, Mesgana Dagnachew, Michael Krause, John A. Hanover
bioRxiv 2022.05.26.493566; doi: https://doi.org/10.1101/2022.05.26.493566

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