Abstract
Mitochondrial antiviral signalling protein (MAVS) acts as a critical adaptor protein to transduce antiviral signalling by physically interacting with activated RIG-I and MDA5 receptors. MAVS executes its functions at the outer membrane of mitochondria to regulate downstream antiviral signalling, indicating that the mitochondria provides a functional platform for innate antiviral signalling transduction. However, little is known about whether and how MAVS-mediated antiviral signalling contributes to mitochondrial homeostasis. Here we show that the activation of MAVS is sufficient to induce autophagic signalling, which may mediate the turnover of the damaged mitochondria. Importantly, we find MAVS directly interacts with LC3 through its LC3-binding motif ‘YxxI’, suggesting that MAVS might act as an autophagy receptor to mediate mitochondrial turnover upon excessive activation of RLR signalling. Furthermore, we provide evidence that both MAVS self-aggregation and its interaction with TRAF2/6 proteins are important for MAVS-mediated mitochondrial turnover. Collectively, our findings suggest that MAVS acts as a potential receptor for mitochondria-associated autophagic signalling to maintain mitochondrial homeostasis.
Highlights
Upon viral infection, the host innate immune system employs several pattern recognition receptors, including membrane-bound Toll-like receptors and cytosolic receptors, such as retinoic-acid-inducible gene-I (RIG-I)-like receptors (RLRs), to recognize conserved molecular signatures [1]
We have previously shown that the activation of MAVS signalling increased reactive oxygen species (ROS) production and induced LC3 puncta formation when GFP-LC3, an autophagy indicator, was co-expressed with MAVS in transfected cells [14]
Accumulating evidence suggest that the proper turnover of mitochondria via the selective autophagy pathway, namely, mitophagy, is important for development and tissue homeostasis [21, 41, 42]
Summary
The host innate immune system employs several pattern recognition receptors, including membrane-bound Toll-like receptors and cytosolic receptors, such as retinoic-acid-inducible gene-I (RIG-I)-like receptors (RLRs), to recognize conserved molecular signatures (pathogen-associated molecular patterns, PAMPs) [1]. Recent studies have identified a number of mitochondria-associated proteins (for example, NLRX1, MFN2, TUFM and COX5B) [11,12,13,14] that interact with and negatively regulate MAVS signalling activity. These findings suggest that mechanisms involving the dynamics of mitochondrial morphology and its quality control appear to contribute to the immune balance in host cells. Other emerging lines of evidence have suggested that the autophagy pathway is engaged in controlling MAVS-mediated antiviral signalling [15]. These findings provide a potential link between mitochondrial homeostasis and MAVS-mediated antiviral signalling; fundamental issues of whether and how MAVS mediates mitochondrial homeostasis remain to be explored
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