Hasan Maroof, Gonugunta Vijay K, Dobbs Nicole, Ali Aktar, Palchik Guillermo, Calvaruso Maria A, DeBerardinis Ralph J, Yan Nan
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):746-751. doi: 10.1073/pnas.1611113114. Epub 2017 Jan 9.
Three-prime repair exonuclease 1 knockout (Trex1) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 background, and many metabolic defects persist in Trex1Irf3 cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.
3'-修复外切核酸酶1基因敲除（Trex1）小鼠患有全身性炎症，这主要是由环磷酸鸟苷-腺苷酸合成酶-干扰素基因刺激因子-TANK结合激酶-干扰素调节因子3（cGAS-STING-TBK1-IRF3）信号通路的慢性激活引起的。我们之前表明，Trex1缺陷细胞的哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）活性降低，但其潜在机制尚不清楚。在这里，我们对Trex1小鼠和细胞进行了详细的代谢分析，结果显示细胞和全身都存在代谢缺陷，包括线粒体呼吸减少以及糖酵解、能量消耗和脂肪代谢增加。我们还通过基因分离炎症和代谢表型，发现Sting缺陷可挽救炎症和代谢表型，而Irf3缺陷仅能在Trex1背景下挽救炎症，并且许多代谢缺陷在Trex1Irf3细胞和小鼠中仍然存在。我们还表明，瘦素缺乏（ob/ob）可增加Trex1小鼠的脂肪生成并延长其存活时间，而不会减轻炎症。从机制上讲，我们确定TBK1是Trex1细胞中mTORC1活性的关键调节因子。总之，我们的数据表明，TBK1的慢性先天性免疫激活会抑制mTORC1活性，导致细胞代谢失调。
