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

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