OGT-induced O-GlcNAcylation of NEK7 protein aggravates osteoarthritis progression by enhancing NEK7/NLRP3 axis.

BACKGROUNDS

The role of O-GlcNAc transferase (OGT)-induced O-linked N-acetylglucosaminylation (O-GlcNAcylation) has been reported in multiple human diseases. However, its specific functions in osteoarthritis (OA) progression remain undetermined.

OBJECTIVE

This study focused on the target proteins of OGT-induced O-GlcNAcylation in OA and the specific functional mechanism.

METHODS

The levels of total O-GlcNAc and OGT were measured in both and OA models using western blot. The effects of OGT knockout on OA progression were detected through Safranin O staining, immunohistochemical staining and OARSI score evaluation. The effects of OGT silencing on LPS-induced chondrocyte injury were assessed by performing loss-of function assays. Co-immunoprecipitation (co-IP) was conducted to verify the effect of OGT-induced O-GlcNAcylation on the interaction between NEK7 and NLRP3. The role of OGT in modulating the O-GlcNAcylation and phosphorylation levels of NEK7 was analysed using western blot.

RESULTS

The OGT-indued O-GlcNAcylation level was increased in both and OA models. Knockout of OGT mitigated OA progression in model mice. Additionally, silencing of OGT suppressed LPS-induced chondrocyte pyroptosis. Moreover, silencing of OGT inhibited the O-GlcNAcylation and enhanced the phosphorylation of NEK7 at S260 site, thereby blocking the binding of NEK7 with NLRP3.

CONCLUSION

OGT-induced NEK7 O-GlcNAcylation promotes OA progression by promoting chondrocyte pyroptosis the suppressing interaction between NEK7 and NLRP3.