Antagonism of ALAS1 by the Measles Virus V protein contributes to degradation of the mitochondrial network and promotes interferon response

• Published in: PLoS pathogens 2023-02, Vol.19 (2), p.e1011170-e1011170
• Main Authors: Khalfi, Pierre, Suspène, Rodolphe, Raymond, Kyle A, Caval, Vincent, Caignard, Grégory, Berry, Noémie, Thiers, Valérie, Combredet, Chantal, Rufie, Claude, Rigaud, Stéphane, Ghozlane, Amine, Volant, Stevenn, Komarova, Anastassia V, Tangy, Frédéric, Vartanian, Jean-Pierre
• Format: Article
• Language: English
• Subjects: 5-Aminolevulinate Synthetase - genetics; 5-Aminolevulinate Synthetase - metabolism; Analysis; Animals; Apoptosis; Bioinformatics; Biological response modifiers; Biology and Life Sciences; Biosynthesis; Catabolism; Cell culture; Complications and side effects; Computer Science; Cytosol; Deoxyribonucleic acid; Development and progression; Disease susceptibility; DNA; DNA, Mitochondrial; DNA-directed RNA polymerase; Double-stranded RNA; Enzymes; Feedback loops; Fractionation; Genes; Genetic aspects; Genetic engineering; Glycine; Health aspects; Heme; Hemoglobin synthesis; Immune response; Immune system; Innate immunity; Interferon; Interferons; Intermediates; Life Sciences; Localization; Measles; Measles virus; Medicine and Health Sciences; Mice; Microbiology and Parasitology; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Negative feedback; Perturbation; Physiological aspects; Proteins; Research and Analysis Methods; Ribonucleic acid; RNA; RNA viruses; Sequence analysis; Succinyl-CoA; Transgenic mice; V protein; Viral proteins; Virology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011170

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.