SNX9 is Required for Fumarate Hydratase-Regulated Mitochondrial RNA (mtRNA) Release and IFN-β production in Macrophages

Fumarate hydratase (FH) has been shown to regulate mitochondrial RNA (mtRNA) release in lipopolysaccharide (LPS)-activated macrophages. In the cytosol, mtRNA activates the nucleic acid-sensing pattern recognition receptors RIG-I, MDA5 and TLR7 inducing IFN-β production. However, the mechanism of mtRNA release is still unclear. Here, we have investigated the role of Sorting Nexin 9 (SNX9) in this process. Silencing SNX9 blocked both the increase in cytosolic mtRNA and IFN-β production in both prolonged LPS stimulation and acute FH inhibition. Mechanistically, FH inhibition drives SNX9 mitochondrial localization 60 minutes after LPS stimulation where it interacts with TMEM11, a mitochondrial protein involved in mitochondrial dynamics. These results provide evidence for a role for SNX9 in the release of mtRNA in response to FH targeting leading to the induction of the anti-viral and immunomodulatory cytokine IFN-β in response to LPS.