糖酵解
免疫系统
厌氧糖酵解
糖基化
癌症研究
生物
瓦博格效应
化学
细胞生物学
生物化学
新陈代谢
免疫学
作者
Qiang Zhu,Jingchao Li,Haofan Sun,Zhiya Fan,Jiating Hu,Siyuan Chai,Bingyi Lin,Liming Wu,Weijie Qin,Yong Wang,Linda C. Hsieh–Wilson,Wen Yi
标识
DOI:10.1073/pnas.2408354121
摘要
Aerobic glycolysis and immune evasion are two key hallmarks of cancer. However, how these two features are mechanistically linked to promote tumor growth is not well understood. Here, we show that the glycolytic enzyme enolase-1 (ENO1) is dynamically modified with an O -linked β- N -acetylglucosamine (O-GlcNAcylation), and simultaneously regulates aerobic glycolysis and immune evasion via differential glycosylation. Glycosylation of threonine 19 (T19) on ENO1 promotes its glycolytic activity via the formation of active dimers. On the other hand, glycosylation of serine 249 (S249) on ENO1 inhibits its interaction with PD-L1, decreases association of PD-L1 with the E3 ligase STUB1, resulting in stabilization of PD-L1. Consequently, blockade of T19 glycosylation on ENO1 inhibits glycolysis, and decreases cell proliferation and tumor growth. Blockade of S249 glycosylation on ENO1 reduces PD-L1 expression and enhances T cell–mediated immunity against tumor cells. Notably, elimination of glycosylation at both sites synergizes with PD-L1 monoclonal antibody therapy to promote antitumor immune response. Clinically, ENO1 glycosylation levels are up-regulated and show a positive correlation with PD-L1 levels in human colorectal cancers. Thus, our findings provide a mechanistic understanding of how O-GlcNAcylation bridges aerobic glycolysis and immune evasion to promote tumor growth, suggesting effective therapeutic opportunities.
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