ISG15 governs mitochondrial function in macrophages following vaccinia virus infection
Entity
UAM. Departamento de Medicina Preventiva y Salud Pública y MicrobiologíaPublisher
Public Library of ScienceDate
2017-10-27Citation
10.1371/journal.ppat.1006651
PLoS Pathogens 13.10 (2017): e1006651
ISSN
1553-7366 (print); 1553-7374 (online)DOI
10.1371/journal.ppat.1006651Funded by
This research is supported by a grant from Spanish Ministry of Economy and Competitiveness (MINECO) to SG (SAF2014-54623-R), and to JV from MINECO (BIO2015-67580-P) and from the Carlos III Institute of Health-Fondo de Investigaciónn Sanitaria (PRB2, IPT13/0001ÐISCIII-SGEFI/FEDER, ProteoRed)Project
Gobierno de España. SAF2014-54623-R; Gobierno de España. BIO2015-67580-P; Gobierno de España. IPT13/0001Editor's Version
https://doi.org/ 10.1371/journal.ppat.1006651Subjects
ISG15; Macrophages; Mitochondrial dysfunction; IFN treatment.; MedicinaRights
© 2017 Baldanta et al.Abstract
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
Files in this item
Google Scholar:Baldanta, Sara
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Fernández-Escobar, Mercedes
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Acín-Pérez, Rebeca
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Albert, Manuel
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Camafeita, Emilio
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Jorge, Inmaculada
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Vázquez, Jesús
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Enríquez, José Antonio
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Guerra, Susana
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