Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing, China.
Mol Immunol. 2022 Jul;147:101-114. doi: 10.1016/j.molimm.2022.04.009. Epub 2022 May 6.
TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1), a nonclassical IκB 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 α-ketoglutarate (α-KG) in macrophages. α-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.
TANK 结合激酶 1（TBK1）是一种非经典 IκB 激酶（IKK），其与 NF-κB 激活物 TRAF 相关，它在炎症中的作用尚未完全阐明。在这里，我们发现 TBK1 通过介导受体相互作用蛋白激酶 3（RIPK3）的磷酸化并促进巨噬细胞内毒素耐受（ET），参与谷氨酰胺的分解代谢。我们发现 TBK1 蛋白可直接与 RIPK3 蛋白相互作用，并在巨噬细胞中介导 RIPK3 的磷酸化。活化的 RIPK3 可直接与谷氨酸脱氢酶 1（GLUD1）结合，GLUD1 是已知催化谷氨酰胺分解的关键酶，以提高其催化活性并增加巨噬细胞中α-酮戊二酸（α-KG）的产生。谷氨酰胺分解产生的α-KG 可促进 M2 激活并限制 M1 极化，从而在促进脂多糖（LPS）诱导的 ET 中发挥关键作用。由于 TBK1 调节 RIPK3 的磷酸化水平，因此过表达 TBK1 可通过谷氨酰胺分解增强巨噬细胞对内毒素的耐受。总的来说，这些发现揭示了一种通过调节谷氨酰胺代谢来控制炎症和诱导 ET 的新机制。
