O-GlcNAc糖基化修饰调控炎症信号通路

O-GlcNAcylation in Regulating Inflammatory Signaling Pathways

O-GlcNAc糖基化修饰指蛋白质的丝氨酸或苏氨酸羟基末端上发生的N-乙酰氨基葡萄糖修饰。O-GlcNAc糖基化修饰广泛影响激酶活性、转录翻译、蛋白质降解等重要生物学途径,但该修饰如何调控炎症信号通路鲜有系统总结。O-GlcNAc糖基化修饰在对应酶作用下数分钟内即可完成一次循环。该修饰与磷酸化、泛素化、甲基化等多种蛋白质翻译后修饰存在串音干扰,共同操控细胞信号通路。目前,O-GlcNAc糖基化修饰参与炎症过程研究大部分聚焦于TLR4/NF-κB信号通路,发现p65蛋白的T352及T305位点的O-GlcNAc糖基化修饰均可促进其核转位,而p65的S536位点发生O-GlcNAc糖基化修饰可抑制其磷酸化激活;亦揭示了O-GlcNAc糖基化修饰调控NF-κB多种上下游因子,改变巨噬细胞极化及炎症反应过程。此外,O-GlcNAc糖基化修饰可干预MAPKs上游激酶(例如MEK2和Ras蛋白等)间接调控MAPKs的激活。O-GlcNAc糖基化修饰不仅深度影响PI3K/AKT多个关键激酶,还可直接调节JAK/STAT信号通路相关的炎症转录因子。真实炎症反应涉及的信号通路远比细胞更复杂和更广泛。体内研究证实,O-GlcNAc糖基化修饰在胰腺、肝、脂肪、肺和肠道等部位的炎性病变中有重要作用。最新研究发现,具备类似O-GlcNAc糖基水解酶活性的肠道细菌,能有效预防宿主结肠炎的发生,证明O-GlcNAc糖基化修饰可介导肠道菌群与宿主炎症相互作用。现有研究结果提示了靶向O-GlcNAc糖基化修饰能为防治炎性疾病提供创新思路。

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.