Dendritic Cells Require PINK1-Mediated Phosphorylation of BCKDE1 a to Promote Fatty Acid Oxidation for Immune Function
Dendritic Cells Require PINK1-Mediated Phosphorylation of BCKDE1 a to Promote Fatty Acid Oxidation for Immune Function
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DOI：
10.3389/fimmu.2019.02386
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发表时间：
2019-10-15
影响因子：
7.3
通讯作者：
de Vries, I. Jolanda M.
中科院分区：
文献类型：
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作者：
Basit, Farhan;de Vries, I. Jolanda M.
toll样受体（TLR）激动剂激活树突状细胞（DCs）可诱导糖酵解代谢重组。该领域的最新发现确定了控制这些代谢适应的机制细节。然而，尚不清楚从氧化磷酸化（OXPHOS）转变为糖酵解是否是dc在遇到病原体时的一般特征。在这里，我们展示了不同TLR的参与在dc中触发了不同的代谢适应。我们证明lps介导的TLR4刺激可诱导dc中的糖酵解。相反，蛋白蛋白- rna复合物（pRNA）激活TLR7/8会导致OXPHOS增加。在机制上，我们发现pRNA刺激以依赖pink1的方式磷酸化BCKDE1 α。pRNA刺激增加支链氨基酸水平和增加脂肪酸氧化。需要增加粮农组织和OXPHOS来激活DC。PINK1缺陷dc转向糖酵解以维持ATP水平和活力。此外，PINK1激酶活性的药理诱导引发了免疫抑制DC的免疫刺激功能。我们的研究结果为差异代谢适应提供了新的见解，揭示了支链氨基酸在调节DC免疫应答中的重要作用。
Dendritic cell (DCs) activation by Toll-like receptor (TLR) agonist induces robust metabolic rewiring toward glycolysis. Recent findings in the field identified mechanistic details governing these metabolic adaptations. However, it is unknown whether a switch to glycolysis from oxidative phosphorylation (OXPHOS) is a general characteristic of DCs upon pathogen encounter. Here we show that engagement of different TLR triggers differential metabolic adaptations in DCs. We demonstrate that LPS-mediated TLR4 stimulation induces glycolysis in DCs. Conversely, activation of TLR7/8 with protamine-RNA complex, pRNA, leads to an increase in OXPHOS. Mechanistically, we found that pRNA stimulation phosphorylates BCKDE1 alpha in a PINK1-dependent manner. pRNA stimulation increased branched-chain amino acid levels and increased fatty acid oxidation. Increased FAO and OXPHOS are required for DC activation. PINK1 deficient DCs switch to glycolysis to maintain ATP levels and viability. Moreover, pharmacological induction of PINK1 kinase activity primed immunosuppressive DC for immunostimulatory function. Our findings provide novel insight into differential metabolic adaptations and reveal the important role of branched-chain amino acid in regulating immune response in DC.