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ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase β-TrCP.

Authors :
Guo T
Zuo Y
Qian L
Liu J
Yuan Y
Xu K
Miao Y
Feng Q
Chen X
Jin L
Zhang L
Dong C
Xiong S
Zheng H
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.

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