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O-GlcNAc Transferase Suppresses Inflammation and Necroptosis by Targeting Receptor-Interacting Serine/Threonine-Protein Kinase 3.
Immunity ( IF 32.4 ) Pub Date : 2019-02-12 , DOI: 10.1016/j.immuni.2019.01.007
Xinghui Li 1 , Wei Gong 2 , Hao Wang 3 , Tianliang Li 1 , Kuldeep S Attri 4 , Robert E Lewis 4 , Andre C Kalil 5 , Fatema Bhinderwala 6 , Robert Powers 6 , Guowei Yin 7 , Laura E Herring 8 , John M Asara 9 , Yu L Lei 10 , Xiaoyong Yang 11 , Diego A Rodriguez 12 , Mao Yang 12 , Douglas R Green 12 , Pankaj K Singh 4 , Haitao Wen 1
Affiliation  

Elevated glucose metabolism in immune cells represents a hallmark feature of many inflammatory diseases, such as sepsis. However, the role of individual glucose metabolic pathways during immune cell activation and inflammation remains incompletely understood. Here, we demonstrate a previously unrecognized anti-inflammatory function of the O-linked β-N-acetylglucosamine (O-GlcNAc) signaling associated with the hexosamine biosynthesis pathway (HBP). Despite elevated activities of glycolysis and the pentose phosphate pathway, activation of macrophages with lipopolysaccharide (LPS) resulted in attenuated HBP activity and protein O-GlcNAcylation. Deletion of O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, led to enhanced innate immune activation and exacerbated septic inflammation. Mechanistically, OGT-mediated O-GlcNAcylation of the serine-threonine kinase RIPK3 on threonine 467 (T467) prevented RIPK3-RIPK1 hetero- and RIPK3-RIPK3 homo-interaction and inhibited downstream innate immunity and necroptosis signaling. Thus, our study identifies an immuno-metabolic crosstalk essential for fine-tuning innate immune cell activation and highlights the importance of glucose metabolism in septic inflammation.

中文翻译:

O-GlcNAc转移酶通过靶向与受体相互作用的丝氨酸/苏氨酸蛋白激酶来抑制炎症和坏死病3。

免疫细胞中葡萄糖代谢的升高代表了许多炎症性疾病(如败血症)的标志性特征。但是,单个葡萄糖代谢途径在免疫细胞活化和炎症过程中的作用仍不完全清楚。在这里,我们证明了与己糖胺生物合成途径(HBP)相关的O联β-N-乙酰氨基葡萄糖(O-GlcNAc)信号传导以前无法识别的抗炎功能。尽管糖酵解和戊糖磷酸途径的活性升高,但用脂多糖(LPS)激活巨噬细胞导致HBP活性减弱和蛋白O-GlcNAcylation。O-GlcNAc转移酶(OGT)的缺失,O-GlcNAc转移蛋白的关键酶,导致先天免疫激活增强,败血性炎症加剧。机械上,苏氨酸467(T467)上丝氨酸-苏氨酸激酶RIPK3的OGT介导的O-GlcNAcylation阻止了RIPK3-RIPK1和RIPK3-RIPK3的均质相互作用,并抑制了下游先天免疫和坏死性信号传导。因此,我们的研究确定了微调先天免疫细胞激活所必需的免疫代谢串扰,并强调了葡萄糖代谢在败血性炎症中的重要性。
更新日期:2019-02-12
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