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Drosophila O-GlcNAcase Mutants Reveal an Expanded Glycoproteome and Novel Growth and Longevity Phenotypes.

ABSTRACT: The reversible posttranslational O-GlcNAc modification of serine or threonine residues of intracellular proteins is involved in many cellular events from signaling cascades to epigenetic and transcriptional regulation. O-GlcNAcylation is a conserved nutrient-dependent process involving two enzymes, with O-GlcNAc transferase (OGT) adding O-GlcNAc and with O-GlcNAcase (OGA) removing it in a manner that's protein- and context-dependent. O-GlcNAcylation is essential for epigenetic regulation of gene expression through its action on Polycomb and Trithorax and COMPASS complexes. However, the important role of O-GlcNAc in adult life and health span has been largely unexplored, mainly due the lack of available model systems. Cataloging the O-GlcNAc proteome has proven useful in understanding the biology of this modification in vivo. In this study, we leveraged a recently developed oga knockout fly mutant to identify the O-GlcNAcylated proteins in adult Drosophilamelanogaster. The adult O-GlcNAc proteome revealed many proteins related to cell and organismal growth, development, differentiation, and epigenetics. We identified many O-GlcNAcylated proteins that play a role in increased growth and decreased longevity, including HCF, SIN3A, LOLA, KISMET, ATX2, SHOT, and FOXO. Interestingly, oga mutant flies are larger and have a shorter life span compared to wild type flies, suggesting increased O-GlcNAc results in increased growth. Our results suggest that O-GlcNAc alters the function of many proteins related to transcription, epigenetic modification and signaling pathways that regulate growth rate and longevity. Therefore, our findings highlight the importance of O-GlcNAc in growth and life span in adult Drosophila.

SUBMITTER: Akan I

PROVIDER: S-EPMC8145559 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Organisms, tissues and cells are genetically programmed to grow to a specific largely pre-set size and shape within the appropriate developmental timing. In the event of mutation, cell death, or tissue damage, the remaining cells may increase their rate of growth to compensate and generate an intact, potentially smaller, tissue or organism in order to achieve the desired size. A delay in the developmental timing could aid in this process. The insulin receptor signalling pathway with its central component, the Akt1 kinase, and endpoint regulator, the transcription factor foxo, plays a significant role in the control of growth. Drosophila melanogaster is an excellent model organism with a well-studied life cycle and a consistently developing compound eye that can undergo analysis to compare changes in the properties of adult ommatidia as an indicator of growth. FINDINGS:Imprecise excision of a PZ P-element inserted in the upstream region of Akt1 generated several novel hypomorphic alleles with internally deleted regions of the Pelement. These mutations lead to small, viable Drosophila that present with delays in development. Suppression of this phenotype by the directed expression of Akt1 (+) indicates that the phenotypes observed are Akt1 dependent. Somatic clones of the eyes, consisting of homozygous tissue in otherwise heterozygous organisms that develop within a standard timeframe, signify that more severe phenotypes are masked by an extension in the time of development of homozygous mutants. Generation of Drosophila having the hypomorphic Akt1 alleles and a null allele of the downstream target foxo result in a phenotype very similar to that of the foxo mutant and do not resemble the Akt1 mutants. CONCLUSION:The developmental delay of these novel Akt1 hypomorphs results in a latent phenotype uncovered by generation of somatic clones. The compensatory growth occurring during the extended time of development appears to be implemented through alteration of foxo activity. Production of clones is an effective and informative way to observe the effects of mutations that result in small, viable, developmentally delayed flies.

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Drosophila O-GlcNAcase Mutants Reveal an Expanded Glycoproteome and Novel Growth and Longevity Phenotypes.

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