Denitrosylation of S-nitrosylated OGT is triggered in LPS-stimulated innate immune response

O-linked N-acetylglucosaminyltransferase (OGT)-mediated protein O-GlcNAcylation has been revealing various aspects of functional significance in biological processes, such as cellular signaling and activation of immune system. We found that OGT is maintained as S-nitrosylated form in resting cells, and its denitrosylation is triggered in innate immune response of lipopolysaccharide (LPS)-treated macrophage cells. S-nitrosylation of OGT strongly inhibits its catalytic activity up to more than 80% of native OGT, and denitrosylation of OGT leads to protein hyper-O-GlcNAcylation. Furthermore, blockage of increased protein O-GlcNAcylation results in significant loss of nitric oxide and cytokine production. We propose that denitrosylation of S-nitrosylated OGT is a direct mechanism for upregulation of OGT activity by which immune defense is critically controlled in LPS-stimulated innate immune response.

► S-nitrosylated OGT (SNO-OGT) in resting state is denitrosylated upon LPS stimulation. ► Denitrosylation of OGT leads to protein hyper-O-GlcNAcylation. ► Attenuation of hyper-O-GlcNAcylation results in abnormality of NFkB activity. ► Protein hyper-O-GlcNAcylation critically functions in NO and cytokine production. ► Denitrosylation of SNO-OGT is a key process for innate immune regulation.