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Antiviral activity of bone morphogenetic proteins and activins.
- Source :
-
Nature microbiology [Nat Microbiol] 2019 Feb; Vol. 4 (2), pp. 339-351. Date of Electronic Publication: 2018 Dec 03. - Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- Antiviral Agents metabolism
Cells, Cultured
Endopeptidases genetics
Hepacivirus drug effects
Hepatitis C drug therapy
Hepatitis C metabolism
Hepcidins genetics
Humans
Interferon Regulatory Factors genetics
Interferon-alpha pharmacology
Interferon-alpha therapeutic use
RNA, Viral metabolism
Signal Transduction genetics
Smad1 Protein genetics
Ubiquitin Thiolesterase
Virus Replication drug effects
Zika Virus drug effects
Activins pharmacology
Antiviral Agents pharmacology
Bone Morphogenetic Protein 6 pharmacology
Gene Expression Regulation drug effects
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2058-5276
- Volume :
- 4
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nature microbiology
- Publication Type :
- Academic Journal
- Accession number :
- 30510168
- Full Text :
- https://doi.org/10.1038/s41564-018-0301-9