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TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology
Molecular Cell ( IF 16.0 ) Pub Date : 2020-11-09 , DOI: 10.1016/j.molcel.2020.10.018
Shasha Chen , Shengduo Liu , Junxian Wang , Qirou Wu , Ailian Wang , Hongxin Guan , Qian Zhang , Dan Zhang , Xiaojian Wang , Hai Song , Jun Qin , Jian Zou , Zhengfan Jiang , Songying Ouyang , Xin-Hua Feng , Tingbo Liang , Pinglong Xu

Mitochondrial morphology shifts rapidly to manage cellular metabolism, organelle integrity, and cell fate. It remains unknown whether innate nucleic acid sensing, the central and general mechanisms of monitoring both microbial invasion and cellular damage, can reprogram and govern mitochondrial dynamics and function. Here, we unexpectedly observed that upon activation of RIG-I-like receptor (RLR)-MAVS signaling, TBK1 directly phosphorylated DRP1/DNM1L, which disabled DRP1, preventing its high-order oligomerization and mitochondrial fragmentation function. The TBK1-DRP1 axis was essential for assembly of large MAVS aggregates and healthy antiviral immunity and underlay nutrient-triggered mitochondrial dynamics and cell fate determination. Knockin (KI) strategies mimicking TBK1-DRP1 signaling produced dominant-negative phenotypes reminiscent of human DRP1 inborn mutations, while interrupting the TBK1-DRP1 connection compromised antiviral responses. Thus, our findings establish an unrecognized function of innate immunity governing both morphology and physiology of a major organelle, identify a lacking loop during innate RNA sensing, and report an elegant mechanism of shaping mitochondrial dynamics.



中文翻译:

TBK1介导的DRP1靶向赋予核酸传感以重编程线粒体动力学和生理学。

线粒体形态迅速转变以控制细胞代谢,细胞器完整性和细胞命运。固有的核酸传感,即监测微生物入侵和细胞损伤的主要和一般机制,是否可以重编程并控制线粒体的动力学和功能,目前尚不清楚。在这里,我们出乎意料地观察到,在激活RIG-I-like受体(RLR)-MAVS信号后,TBK1直接磷酸化DRP1 / DNM1L,从而禁用了DRP1,阻止了其高阶低聚和线粒体断裂功能。TBK1-DRP1轴对于大型MAVS聚集体的组装和健康的抗病毒免疫以及营养物触发的线粒体动力学和细胞命运测定的基础至关重要。模仿TBK1-DRP1信号的敲除(KI)策略产生显性阴性表型,让人联想到人类DRP1先天性突变,同时中断TBK1-DRP1连接破坏了抗病毒反应。因此,我们的发现建立了先天免疫功能,它控制着主要细胞器的形态和生理,无法识别其功能,在先天RNA感应过程中发现了缺乏的环,并报道了塑造线粒体动力学的优美机制。

更新日期:2020-12-03
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