Antiviral activity of bone morphogenetic proteins and activins
| Autor: | Hal Drakesmith, Chia Chi Sun, Diego Martines, Marco Binder, Narayan Ramamurthy, Cynthia Sandor, L A Eddowes, Slobodan Vukicevic, Stephane Chevaliez, Andrew E. Armitage, Jamie Frankish, João Arezes, Jan Rehwinkel, J. Crowe, Jodie L. Babitt, Caleb Webber, Matthew W. Lawless, Eleni Giannoulatou, John Ryan, Hannah T Baddock, Paul Klenerman, Maria Teresa Giordani, Herbert Y. Lin, Dahlene N. Fusco, Peter J. McHugh, Owens Bmj., Paolo Fabris, K Al-Hourani, Raymond T. Chung, S Boninsegna |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Microbiology (medical)
animal structures Bone Morphogenetic Protein 6 Immunology SMAD Hepacivirus Bone morphogenetic protein Virus Replication Applied Microbiology and Biotechnology Microbiology Antiviral Agents Article Smad1 Protein 03 medical and health sciences Downregulation and upregulation Hepcidins Interferon Hepcidin Endopeptidases Genetics medicine Humans Cells Cultured 030304 developmental biology 0303 health sciences biology 030306 microbiology Interferon-alpha Cell Biology Zika Virus Hepatitis C Activins Bone morphogenetic protein 6 IRF1 Gene Expression Regulation Interferon Regulatory Factors embryonic structures Cancer research biology.protein RNA Viral Ubiquitin Thiolesterase Interferon regulatory factors medicine.drug Signal Transduction |
| ISSN: | 2058-5276 |
| DOI: | 10.1038/s41564-018-0301-9 |
| Popis: | Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN. |
| Databáze: | OpenAIRE |
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