O-GlcNAcylation of small heat shock proteins enhances their anti-amyloid chaperone activity

A major role for the intracellular posttranslational modification O-GlcNAc appears to be the inhibition of protein aggregation. Most of the previous studies in this area have focused on O-GlcNAcylation of the amyloid-forming proteins themselves. Here, we use synthetic protein chemistry to discover that O-GlcNAc also activates the anti-amyloid activity of certain small heat shock proteins (sHSPs), a potentially more important modification event that can act broadly and substoichiometrically. More specifically, we find that O-GlcNAcylation increases the ability of sHSPs to block the amyloid formation of both α-synuclein and Aβ. Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology.