O-Glucose Glycans in Drosophila Notch Signaling

Abstract

O-glucose glycans are a type of O-linked glycan identified on epidermal growth factor-like (EGF) repeats. In work performed in Drosophila, the roles of O-glucose glycans and their corresponding glycosyltransferases during animal development were analyzed. O-glucose is a high-occupancy sugar modification added by the protein O-glucosyltransferase Rumi (POGLUT1 inmammals). The Notch receptor is a biologically relevant target for O-glucose modifications, and O-glucose residues on Notch function additively and/or redundantly to activateNotch signaling in a temperature-dependent manner. Current data suggest that O-glucose residues regulate Notch activation by altering the conformation of the Notch extracellular domain to promote efficient processing of Notch at a step after ligand binding and before S3 cleavage.O-glucose can also act as a substrate for xylosemodification by the fly glucoside xylosyltransferase Shams (GXYLT1/2 in mammals). Unlike glucose modifications, which promote Notch signaling in all contexts examined thus far, xylose modifications inhibitNotch signaling in certain contexts.Moreover, while O-glucose residues are distributed across the Notch extracellular domain, xylose residues are only present in a specific domain of the Drosophila Notch, namely, EGF14-20. The contrasting roles of glucose and xylose demonstrate the role of O-glucose glycans in finely modulating Drosophila Notch signaling.