ALOX15 Enhances MAVS-mediated IFN beta Signaling Against RNA Viruses

In a recent Nature Immunology study, Weng et al. identify arachidonate lipoxygenase-15 (ALOX15) as a previously unrecognized regulator of mitochondrial antiviral immunity (1). Using ferroptosis-related gene screening, viral infection models, primary immune cells, patient PBMCs, knockout mice, and protein-interaction assays, the authors show that host ALOX15 enhances RIG-I-MAVS-dependent IFNβ production during influenza virus infection. This function is independent of its canonical lipid peroxidation activity. After RNA virus challenge, the authors found that ALOX15 translocates to mitochondria, associates with polymerized MAVS, and displaces deubiquitinase USP19. This potentiates MAVS K63-linked ubiquitination and aggregation, resulting in amplified MAVS antiviral signaling. In vivo, Alox15 deficiency increased susceptibility to H1N1 infection, whereas lung-directed Alox15 restoration improved antiviral defense. The study further proposes a host-directed therapeutic strategy combining ALOX15 transcriptional activation with enzymatic inhibition.