Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P  

作　　者：Yuan-li Ai Wei-jia Wang Fan-jian Liu Wei Fang Hang-zi Chen Liu-zheng Wu Xuehui Hong Yuekun Zhu Ci-xiong Zhang Long-yu Liu Wen-bin Hong Bo Zhou Qi-tao Chen Qiao Wu 

机构地区：[1]State Key Laboratory of Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen,Fujian,China [2]Department of Gastrointestinal Surgery,Zhongshan Hospital of Xiamen University,School of Medicine,Xiamen University,Xiamen,Fujian,China [3]Department of Colorectal Surgery,The First Affiliated Hospital of Harbin Medical University,Harbin,Heilongjiang,China

出　　处：《Cell Research》2023年第12期904-922,共19页细胞研究（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China and the Ministry of Science and Technology of China(U1905206,2020YFA0803403,82021003 to Q.W.,82073017 to W.J.W.,and 82122046,82072727 to X.H.).

摘　　要：Pyroptosis is a type of regulated cell death executed by gasdermin family members.However,how gasdermin-mediated pyroptosis is negatively regulated remains unclear.Here,we demonstrate that mannose,a hexose,inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase(AMPK).Mechanistically,mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate(GlcNAc-6P),which binds AMPK to facilitate AMPK phosphorylation by LKB1.Activated AMPK then phosphorylates GSDME at Thr6,which leads to blockade of caspase-3-induced GSDME cleavage,thereby repressing pyroptosis.The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDME^(T6E) or GSDME^(T6A) knock-in mice.In mouse primary cancer models,mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin-or oxaliplatin-induced tissue toxicity without impairing antitumor effects.The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy.Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK,and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

关 键 词：CHEMOTHERAPY INTESTINE AMPK 

分 类 号：Q2[生物学—细胞生物学]