Fig. 2

O-GlcNAcylation orchestrates immunity. a HSCs are able to self-renew and differentiate into all blood cell lineages. OGA controls the homeostasis of O-GlcNAcylation, which affects the gene transcription, such as fibroblast growth factor 3 (Fgf3) and solute carrier family 1, member 5 (Slc1a5), to regulate self-renewal and nutrient transport of HSCs. b In macrophages, OGT is de-nitrosylated after LPS treatment, which results in O-GlcNAcylation and activation of NF-κB. O-GlcNAcylation of STAT3 inhibits its phosphorylation, leading to decreased IL-10 production and increased pro-inflammatory cytokine production (left panel). In certain scenarios, O-GlcNAcylation also has an anti-inflammatory function in macrophages. GlcN-induced hyper-O-GlcNAcylation inhibits NF-κB-mediated iNOS expression. Moreover, O-GlcNAcylation of RIPK3 inhibits RIPK3-RIPK1 complex formation and thus reduces necroptosis-induced inflammation. The antiviral response of macrophages is also regulated by O-GlcNAcylation (middle panel). Upon RNA virus infection, MAVS is modified by OGT, which is essential for K63-linked ubiquitination-mediated MAVS activation. This biochemical reaction enhances downstream IFN production via RIG-I signaling (right panel). cO-GlcNAcylation is rapidly increased after neutrophils are activated, which promotes the chemotaxis and cellular mobility of neutrophils. dO-GlcNAcylation may inhibit NK differentiation by increasing the stability of EZH2. In addition, O-GlcNAcylation seems to reduce the cytotoxic activity of NK cells. e During T cell development in thymus, O-GlcNAcylation is required for homeostasis of ETPs. Notch signaling promotes the uptake of glucose (Glc) and glutamine (Gln), which leads to protein O-GlcNAcylation, enhanced β selection, and rapid self-renewal of DN4. After TCR rearrangement, O-GlcNAcylation promotes positive selection and mature single positive T cell development (left panel). Protein O-GlcNAcylation is increased when T cells are activated. O-GlcNAcylation is required for activation of many transcription factors, such as NFAT, c-Rel and c-Myc in activated T cells (upper right panel). Notably, O-GlcNAcylation also increases the expression of RORγt and FOXP3 in Th17 and Treg cells (lower right panel). f In B cell lineages, O-GlcNAcylation is upregulated in pre-B cells, thereby promoting the proliferation of pre-B cells through elevating c-Myc expression. Moreover, O-GlcNAcylation regulates BAFF signaling to maintain homeostasis of mature B cells in spleen and bone marrow (left panel). When B cells are activated through BCR signaling, Lyn is modified by OGT, which recruits SYK and activates BCR downstream signaling. NFAT and NFκB are activated by O-GlcNAcylation in activated B cells, which mediates B cell proliferation. O-GlcNAcylation is also involved in BCR crosslinking-induced apoptosis. O-GlcNAc modification of LSP1 recruits PKCβ1, which phosphorylates LSP1 and contributes to B cell apoptosis (right panel)