TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology
- 9 November 2020
- journal article
- research article
- Published by Elsevier BV in Molecular Cell
- Vol. 80 (5), 810-827.e7
- https://doi.org/10.1016/j.molcel.2020.10.018
Abstract
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.Keywords
Funding Information
- National Natural Science Foundation of China
This publication has 96 references indexed in Scilit:
- Structural Basis for the Activation of Innate Immune Pattern-Recognition Receptor RIG-I by Viral RNACell, 2011
- Structural Insights into RNA Recognition by RIG-ICell, 2011
- Mapping a Dynamic Innate Immunity Protein Interaction Network Regulating Type I Interferon ProductionImmunity, 2011
- MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune ResponseCell, 2011
- RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunityCurrent Opinion in Virology, 2011
- Pattern Recognition Receptors and InflammationCell, 2010
- Mitochondrial dynamics regulate the RIG‐I‐like receptor antiviral pathwayEMBO Reports, 2009
- Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane PermeabilizationDevelopmental Cell, 2008
- VISA Is an Adapter Protein Required for Virus-Triggered IFN-β SignalingMolecular Cell, 2005
- Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3Cell, 2005