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Dryad

Itaconate drives mtRNA-mediated Type I interferon production via inhibition of succinate dehydrogenase

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Sep 12, 2024 version files 13.53 MB

Abstract

Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages. It has been shown to have immunomodulatory properties, although the underlying mechanisms are not fully elucidated. Here, we have investigated how itaconate regulates type I interferon production. Using pharmacological and genetic approaches, we have found that inhibition of succinate dehydrogenase (SDH) is required for this response. SDH inhibition by itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. Following this, the dsRNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Inhibition of SDH by itaconate links TCA cycle modulation to type I Interferon production via mtRNA.