TBK1 participates in glutaminolysis by mediating the phosphorylation of RIPK3 to promote endotoxin tolerance

作者全名："Pan, Lehan; Yang, Lian; Yi, Zhujun; Zhang, Wenfeng; Gong, Jianping"

作者地址："[Pan, Lehan; Yang, Lian; Yi, Zhujun; Zhang, Wenfeng; Gong, Jianping] Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, 76 Linjiang Rd, Chongqing 400016, Peoples R China; [Yi, Zhujun] Chongqing Univ, Dept Hepatobiliary Surg, Three Gorges Hosp, Chongqing, Peoples R China"

通信作者："Zhang, WF; Gong, JP (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, 76 Linjiang Rd, Chongqing 400016, Peoples R China."

来源：MOLECULAR IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000802859000001

JCR分区：Q3

影响因子：3.6

年份：2022

卷号：147

期号：　

开始页：101

结束页：114

文献类型：Article

关键词：TBK1; Endotoxin tolerance; Sepsis; RIPK3; GLUD1; ?-KG

摘要："TRAF-associated NF-kappa B activator (TANK)-binding kinase 1 (TBK1), a nonclassical I kappa B kinase (IKK), and its effect on inflammation have not been entirely clarified. Here, we identified that TBK1 participates in the catabolism of glutamine by mediating the phosphorylation of receptor-interacting protein kinase 3 (RIPK3) and promoting macrophage endotoxin tolerance (ET). We found that the TBK1 protein directly interacts with the RIPK3 protein and mediates the phosphorylation of RIPK3 in macrophages. Activated RIPK3 can directly bind to glutamate dehydrogenase 1 (GLUD1), which is known to be a critical enzyme for catalyzing glutamine decomposition, to improve its catalytic activity and increase the production of alpha-ketoglutarate (alpha-KG) in macrophages. alpha-KG generated from glutaminolysis can promote M2 activation and restrict M1 polarization, which plays a crucial role in promoting lipopolysaccharide (LPS)-induced ET. As a result of TBK1 regulating the phosphorylation level of RIPK3, overexpressed TBK1 could enhance the tolerance of macrophages to endotoxin through glutaminolysis. Overall, these findings reveal a novel mechanism for the metabolic control of inflammation and for the induction of ET by modulating glutamine metabolism."

基金机构："National Natural Science Founda-tion of China [81971880, 81801963]; China Postdoctoral Science Foundation [2019M653352]"

基金资助正文：Funding This study was supported by the National Natural Science Founda-tion of China (Nos. 81971880 and 81801963) and China Postdoctoral Science Foundation (2019M653352) .