ISG15 governs mitochondrial function in macrophages following vaccinia virus infection

PLoS Pathogens

Manuel Albert¹  Mercedes Fernández-Escobar²  Emilio Camafeita²  Sara Baldanta²  Rebeca Acín-Perez³  Inmaculada Jorge⁴  José Antonio Enríquez⁴  Susana Guerra⁵  Jesús Vázquez⁵ 

[1] Madrid (SPAIN);Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma, Madrid, Spain;Functional Genetics of the Oxidative Phosphorylation System, Centro Nacional de Investigaciones Cardiovasculares Carlos III;Laboratory of Cardiovascular Proteomics, Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Madrid (SPAIN);Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and CIBER de Enfermedades Cardiovasculares (CIBER-CV), Madrid (SPAIN)

关键词: Mitochondria;    Macrophages;    Dehydrogenases;    Interferons;    Respiratory infections;    Apoptosis;    Immune response;    Viral replication;   

DOI  :  10.1371/journal.ppat.1006651

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY