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ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase β-TrCP.
- Source :
-
Nature microbiology [Nat Microbiol] 2019 Nov; Vol. 4 (11), pp. 1872-1884. Date of Electronic Publication: 2019 Apr 15. - Publication Year :
- 2019
-
Abstract
- Outbreaks of viral infections are a global health burden. Although type I interferon (IFN-I) exerts broad-spectrum antiviral effects, its antiviral efficacy in host cells is largely restricted by viruses. How the antiviral efficacy of IFN-I can be improved remains to be explored. Here, we identified the ADP-ribosyltransferase poly(ADP-ribose) polymerase family member 11 (PARP11) as a potent regulator of IFN-I antiviral efficacy. PARP11 does not restrict IFN-I production induced by vesicular stomatitis virus or Sendai virus but inhibits the strength of IFN-I-activated signalling. Mechanistically, PARP11 mono-ADP-ribosylates the ubiquitin E3 ligase β-transducin repeat-containing protein (β-TrCP). Mono-ADP-ribosylation of β-TrCP promotes IFNα/β receptor subunit 1 (IFNAR1) ubiquitination and degradation. Moreover, PARP11 expression is upregulated by virus infections, including vesicular stomatitis virus, herpes simplex virus-1 and influenza A virus, thus promoting ADP-ribosylation-mediated viral evasion. We further highlight the potential for repurposing clinical ADP-ribosylation inhibitors. We found that rucaparib can target PARP11 to stabilize IFNAR1 and therefore exhibits efficient enhancement of IFN-I signalling and the host antiviral response. Consequently, rucaparib renders mice more resistant to viral infection. Our study updates the understanding of how β-TrCP regulates its substrates and may provide a druggable target for improving IFN antiviral efficacy.
- Subjects :
- ADP-Ribosylation
Animals
Cells, Cultured
Chlorocebus aethiops
Disease Models, Animal
HEK293 Cells
Hep G2 Cells
Humans
Indoles administration & dosage
Indoles pharmacology
Mice
Proteolysis
Sendai virus immunology
Signal Transduction
Ubiquitination
Vero Cells
Vesiculovirus immunology
Virus Diseases drug therapy
Virus Diseases metabolism
Interferon Type I metabolism
Poly(ADP-ribose) Polymerases metabolism
Receptor, Interferon alpha-beta chemistry
Receptor, Interferon alpha-beta metabolism
Virus Diseases immunology
beta-Transducin Repeat-Containing Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2058-5276
- Volume :
- 4
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nature microbiology
- Publication Type :
- Academic Journal
- Accession number :
- 30988430
- Full Text :
- https://doi.org/10.1038/s41564-019-0428-3