earticle

영어

Post-translational modifications, including O-GlcNAcylation, play fundamental roles in modulating cellular events, including transcription, signal transduction, and immune signaling. O-GlcNAcylation is PTMs on proteins that rapidly respond to extracellular stimuli. Although several molecular targets of O-GlcNAcylation associated with pathogen-induced innate immune responses have been reported, it is poorly understood how a host modulates intracellular O-GlcNAcylation to optimize pathogen-induced innate immune response and necroptotic cell death. Here we show that RNA virus infection or gram-negative bacterial infection induces a decrease in O-GlcNAcylation levels in several types of cells. Especially, we show that epithelial cells reduce OGT expression during the late phases of Sendai virus infection via RIG-I-like receptor activation. Downregulation of OGT expression led to a decrease in O-GlcNAcylation of MAVS during RNA virus infection. Moreover, we identified a heavily O-GlcNAcylated serine-rich region between amino acids 249-257 of the mitochondrial antiviral signaling protein (MAVS) and that it inhibits the formation of MAVS aggregates which are crucial for activating MAVS. O-GlcNAcylation of the serine-rich region of MAVS also suppresses its interaction with TRAF3; this prevents IRF3 activation and production of interferon-β. On the other hand, host cells suffer from sepsis, a serious inflammatory disease in response to pathogenic infection with Escherichia coli or staphylococcus. In this study, we demonstrate that O-GlcNAcylation suppresses sepsis-induced blood cell dysfunction. Moreover, we observe that the host accelerates its own immune response by reducing cellular O-GlcNAcylation in order to fight pathogen infections. Taken together, we suggest that it is essential to maintain host O-GlcNAc homeostasis in order to avoid excessive or abnormal immune responses.