O⁃GlcNAcylation in Regulating Inflammatory Signaling Pathways / 中国生物化学与分子生物学报

ABSTRACT

O⁃GlcNAcylation is an O⁃linked⁃β⁃N⁃acetylglucosamine modification attached to the hydroxyl group of serine or threonine residue within the nuclear or cytoplasmic proteins. O⁃GlcNAcylation profoundly influences important biological events, including kinase activity, transcription and translation, and protein degradation. However, there are few summarized reviews on how O⁃GlcNAcylation modulates signaling pathways associated with inflammatory responses. Due to the attachment and removal of the sugar group catalyzed by O⁃GlcNAc transferase and O⁃GlcNAcase, O⁃GlcNAcylation cycles rapidly with a short half⁃life time (within minutes). Therefore, O⁃GlcNAcylation plays a crucial role in various signaling pathways via intricate cross⁃talking with other post⁃translational modifications of protein, such as phosphorylation, acetylation, ubiquitylation, and methylation. Currently, most researchers focused on the Toll⁃like receptor (TLR)⁃initiated NF⁃κB signaling when it comes to the relationship between O⁃GlcNAcylation and inflammation. Evidence has shown that O⁃GlcNAcylation at T352 or at T305 on p65 promotes its nuclear translocation activity, while O⁃GlcNAcylation at S536 blocks the activation of p65 by competing with phosphorylation. Meanwhile, O⁃GlcNAcylation modulates upstream and downstream regulators of NF⁃κB and then governs the polarization of M1/ M2 macrophage and the progress of inflammation reactions. Furthermore, O⁃GlcNAcylation indirectly participates in the kinase activation of MAPKs by interfering with the proteins at the upper reaches (i. e. MEK2 and Ras proteins). Besides, O⁃GlcNAcylation has a profound influence on multiple kinases of PI3K/ AKT signaling. Nevertheless, O⁃GlcNAcylation manipulates inflammation⁃associated transcriptional factors on the JAK/ STAT pathway. Comparatively, the involved signaling transduction for the inflammatory response in vivo is far more complicated and multidimensional than that in vitro. And O⁃GlcNAcylation is widely involved with the onset and development of inflammatory diseases located at the pancreas, liver, lung, gut, and adipose tissues. Novel research has firstly found that gut bacteria expressing O⁃GlcNAcase⁃like hydrolases exert potent prevention on mouse colitis induced by different chemical drugs, which indicates the mediating role of O⁃GlcNAcylation in mutual interactions between gut microbiota and host inflammation. In summary, recent findings provided a novel strategy for preventing and treating inflammatory diseases by targeting O⁃GlcNAcylation.