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Hsp9 regulates O-linked beta-N-acetylglucosamine transferase a novel mechanism of modulation of protein O-linked beta-N-acetylglucosamine modification in endothelial cells

, : Hsp9 regulates O-linked beta-N-acetylglucosamine transferase a novel mechanism of modulation of protein O-linked beta-N-acetylglucosamine modification in endothelial cells.

O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins is involved in many important cellular processes. Increased O-GlcNAc has been implicated in major diseases, such as diabetes and its complications and cardiovascular and neurodegenerative diseases. Recently, we reported that O-GlcNAc modification occurs in the proteasome and serves to inhibit proteasome function by blocking the ATPase activity in the 19S regulatory cap, explaining, at least in part, the adverse effects of O-GlcNAc modification and suggesting that downregulating O-GlcNAc might be important in the treatment of human diseases. In this study, we report on a novel mechanism to modulate cellular O-GlcNAc modification, namely through heat shock protein 9 (Hsp9) inhibition. We observed that O-linked β-N-acetylglucosamine transferase (OGT) interacts with the tetratricopeptide repeat binding site of Hsp9. Inhibition of Hsp9 by its specific inhibitors, radicicol or 17-N-allylamino-17-demethoxygeldanamycin, destabilized OGT in primary endothelial cell cultures and enhanced its degradation by the proteasome. Furthermore, Hsp9 inhibition downregulated O-GlcNAc protein modifications and attenuated the high glucose-induced increase in O-GlcNAc protein modification, including high glucose-induced increase in endothelial or type 3 isoform of nitric oxide synthase (eNOS) O-GlcNAcylation. These results suggest that Hsp9 is involved in the regulation of OGT and O-GlcNAc modification and that Hsp9 inhibitors might be used to modulate O-GlcNAc modification and reverse its adverse effects in human diseases.


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