C-terminal tail of MAVS dictates organelle targeting and innate immune response

MAVS is a mitochondrial and peroxisomal protein that adapts innate RNA sensing by RIG-I-like receptors to downstream signalling. MAVS aggregation is required for the propagation of the activation signal, however whether this requirement varies with respect to subcellular localization remains unclear. MAVS mutants were expressed in transfected, lentivirus-transduced and Sendai virus-infected cells. They were then analysed for subcellular localization by confocal immunofluorescence microscopy, for aggregation by semi-denaturing gel electrophoresis, and for activation of type I interferon production by Western blotting of phosphorylated IRF3 and ELISA of interferon β. We identified that MAVS aggregation is required for innate immune signalling triggered by mitochondrial but not peroxisomal MAVS. An aggregation-deficient mutant of peroxisomal MAVS retained its ability to induce type I interferon production. We further demonstrated that the magnitude of the activation signal and the distribution of MAVS to mitochondria and peroxisomes are governed by the tail charge at the C-terminus of MAVS. An increase in tail charge directs MAVS to peroxisomes predominantly, leading to a more modest activation of innate immune signalling. These results suggest that MAVS displays compartment-specific properties that are mechanistically and functionally distinct in RNA sensing.