Figure 9. High glucose promotes A20 O-glycosylation, ubiquitination and proteasomal degradation in EC and SMC.

High glucose increases protein O-GlcNAcylation, including that of A20 and possibly other E3 Ubiquitin ligases. This leads to increased A20 ubiquitination either through auto-ubiquitination or increased activity of other O-GlcNAcylated E3 ubiquitin ligases. This targets A20 for degradation in the proteasome. Blockade of O-GlcNAcylation using DON, upstream of A20 Ubiquitination, or inhibition of proteasome activity, using MG132, downstream of A20 ubiquitination would inhibit its proteasomal degradation, restoring its expected protein levels.