MAVS oligomerization drives a faster and more efficient antiviral signaling activation at peroxisomes compared to mitochondria.

Peroxisomes and mitochondria are important platforms for antiviral signal transduction, as detection of cytosolic viral RNA by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) induces the activation of the mitochondrial antiviral signaling adaptor (MAVS) at both organelles. To decisively elucidate the mechanistic differences and similarities in kinetics and end products between these two pathways, we developed a doxycycline-inducible system that allows for precise control of MAVS expression and activation at either peroxisomes or mitochondria, in a timely manner, and across various cell types. Our findings demonstrate that both peroxisomal and mitochondrial MAVS induce type I and III interferon-dependent antiviral signaling and that the peroxisomal signaling occurs significantly faster than its mitochondrial counterpart. Importantly, using not only the doxycycline-inducible system but also the conventional activation of the MAVS pathway through direct stimulation of RIG-I-like receptors, we demonstrate that the rapid and robust antiviral response resulting from peroxisomal MAVS activation is mechanistically due to the faster oligomerization of MAVS at the membranes of this organelle, when compared to mitochondria. These data emphasize the versatility and speed of the peroxisome-dependent antiviral response and may lead to the identification of specific targets to develop novel host-directed antiviral strategies.