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oai:repisalud.isciii.es:20.500.12105/64962024-09-27T08:38:56Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605col_20.500.12105_19607

00925njm 22002777a 4500 dc Baldanta, Sara author Fernandez-Escobar, Mercedes author Acin-Perez, Rebeca author Albert, Manuel author Camafeita, Emilio author Jorge, Inmaculada author Vazquez, Jesus author Enriquez, Jose Antonio author Guerra, Susana author 2017 The interferon (IFN)-stimulated gene 15 (ISG15) encodes one of the most abundant proteins induced by interferon, and its expression is associated with antiviral immunity. To identify protein components implicated in IFN and ISG15 signaling, we compared the proteomes of ISG15(-/-) and ISG15(+/+) bone marrow derived macrophages (BMDM) after vaccinia virus (VACV) infection. The results of this analysis revealed that mitochondrial dysfunction and oxidative phosphorylation (OXPHOS) were pathways altered in ISG15(-/-) BMDM treated with IFN. Mitochondrial respiration, Adenosine triphosphate (ATP) and reactive oxygen species (ROS) production was higher in ISG15(+/+) BMDM than in ISG15(-/-) BMDM following IFN treatment, indicating the involvement of ISG15-dependent mechanisms. An additional consequence of ISG15 depletion was a significant change in macrophage polarization. Although infected ISG15(-/-) macrophages showed a robust proinflammatory cytokine expression pattern typical of an M1 phenotype, a clear blockade of nitric oxide (NO) production and arginase- 1 activation was detected. Accordingly, following IFN treatment, NO release was higher in ISG15(+/+) macrophages than in ISG15(-/-) macrophages concomitant with a decrease in viral titer. Thus, ISG15(-/-) macrophages were permissive for VACV replication following IFN treatment. In conclusion, our results demonstrate that ISG15 governs the dynamic functionality of mitochondria, specifically, OXPHOS and mitophagy, broadening its physiological role as an antiviral agent. PLoS Pathog. 2017; 13(10):e1006651 10.1371/journal.ppat.1006651 1553-7374 1553-7366 PLOS PATHOGENS 29077752 http://hdl.handle.net/20.500.12105/6496 UBIQUITIN-LIKE PROTEIN INTERFERON-STIMULATED GENE INNATE ANTIVIRAL RESPONSE CONJUGATION SYSTEM IN-VIVO QUANTITATIVE PROTEOMICS PEPTIDE IDENTIFICATION VIRAL RESISTANCE IMMUNE-SYSTEM HOST-DEFENSE ISG15 governs mitochondrial function in macrophages following vaccinia virus infection