부산대학교 도서관

Viruses have evolved countless mechanisms to subvert and impair the host innate immune response. Measles virus (MeV), an enveloped, non-segmented, negative-strand RNA virus, alters the interferon response through different mechanisms, yet no viral protein has been described as directly targeting mitochondria. Among the crucial mitochondrial enzymes, 5′-aminolevulinate synthase (ALAS) is an enzyme that catalyzes the first step in heme biosynthesis, generating 5′-aminolevulinate from glycine and succinyl-CoA. In this work, we demonstrate that MeV impairs the mitochondrial network through the V protein, which antagonizes the mitochondrial enzyme ALAS1 and sequesters it to the cytosol. This re-localization of ALAS1 leads to a decrease in mitochondrial volume and impairment of its metabolic potential, a phenomenon not observed in MeV deficient for the V gene. This perturbation of the mitochondrial dynamics demonstrated both in culture and in infected IFNAR−/− hCD46 transgenic mice, causes the release of mitochondrial double-stranded DNA (mtDNA) in the cytosol. By performing subcellular fractionation post infection, we demonstrate that the most significant source of DNA in the cytosol is of mitochondrial origin. Released mtDNA is then recognized and transcribed by the DNA-dependent RNA polymerase III. The resulting double-stranded RNA intermediates will be captured by RIG-I, ultimately initiating type I interferon production. Deep sequencing analysis of cytosolic mtDNA editing divulged an APOBEC3A signature, primarily analyzed in the 5'TpCpG context. Finally, in a negative feedback loop, APOBEC3A an interferon inducible enzyme will orchestrate the catabolism of mitochondrial DNA, decrease cellular inflammation, and dampen the innate immune response. Author summary: As viruses evolve within the confines of an arms race with the host immune system, they develop means to evade or counteract detection by the immune systems, thus facilitating their replication. In this light, many viruses have been described to encode proteins which target the mitochondrial network, a key hub in immune signaling. Previous work has highlighted the ability of MeV to interact with mitochondria, although the mechanism of perturbation remained elusive. Here we show that the MeV-V protein antagonizes the mitochondrial ALAS1 enzyme and relocalizes it to the cytosol, leading to an alteration of the mitochondrial network. We found that this disruption will induce a release of mitochondrial DNA (mtDNA), constituting a potential danger signal for the infected cell. By investigating the cascade of innate immune sensors triggered by mtDNA in the cytosol, we further show that the endogenous APOBEC3A cytidine deaminase is induced to target the released cytosolic mtDNA, attenuating the danger signal, and reducing cellular inflammation. Our study provides new mechanistic insight into the interaction of MeV with mitochondrial proteins, adding to the ever-growing repertoire of viral strategies to directly or indirectly target this organelle. [ABSTRACT FROM AUTHOR]