Proline Catabolism Modulates Innate Immunity in Caenorhabditis elegans

Metabolic pathways are regulated to fuel or instruct the immune responses to pathogen threats. However, the regulatory roles for amino acid metabolism in innate immune responses remains poorly understood. Here, we report that mitochondrial proline catabolism modulates innate immunity in Caenorhabditis elegans. Modulation of proline catabolic enzymes affects host susceptibility to bacterial pathogen Pseudomonas aeruginosa. Mechanistically, proline catabolism governs reactive oxygen species (ROS) homeostasis and subsequent activation of SKN-1, a critical transcription factor regulating xenobiotic stress response and pathogen defense. Intriguingly, proline catabolism-mediated activation of SKN-1 requires cell-membrane dual-oxidase Ce-Duox1/BLI-3, highlighting the importance of interaction between mitochondrial and cell-membrane components in host defense. Our findings reveal how animals utilize metabolism of a single amino acid to defend against a pathogen and identify proline catabolism as a component of innate immune signaling.