TBK1 participates in glutaminolysis by mediating the phosphorylation of RIPK3 to promote endotoxin tolerance
TBK1 participates in glutaminolysis by mediating the phosphorylation of RIPK3 to promote endotoxin tolerance
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DOI：
10.1016/j.molimm.2022.04.009
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发表时间：
2022-05-06
影响因子：
3.6
通讯作者：
Gong, Jianping
中科院分区：
文献类型：
--
作者：
Pan, Lehan;Yang, Lian;Gong, Jianping
TRAF相关的核因子-kappaB激活物(TANK)结合激酶1(TBK1)是一种非经典的Ikappa B激酶(IKK)，其在炎症反应中的作用尚未完全阐明。在此，我们证实了TBK1通过介导受体相互作用蛋白激酶3(RIPK3)的磷酸化和促进巨噬细胞内毒素耐受(ET)来参与谷氨酰胺的分解代谢。我们发现，TBK1蛋白直接与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可以直接与谷氨酸脱氢酶1(GLUD1)结合，从而提高其催化活性，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活化，抑制M1极化，在促进内毒素(LPS)诱导的ET中起着至关重要的作用。通过调节RIPK3的磷酸化水平，过表达的TBK1可通过谷氨酰胺降解增强巨噬细胞对内毒素的耐受性。总体而言，这些发现揭示了通过调节谷氨酰胺代谢来控制炎症的代谢和诱导ET的新机制。
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.