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

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.

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Fig. 1: PARP11 inhibits the IFN-I-activated signalling pathway.
Fig. 2: PARP11 restricts IFN-I-induced antiviral efficacy.
Fig. 3: PARP11 promotes IFNAR1 ubiquitination and regulates the protein levels of IFNAR1 and β-TrCP.
Fig. 4: PARP11 mono-ADP-ribosylates β-TrCP both in vivo and in vitro.
Fig. 5: β-TrCP mono-ADP-ribosylation by PARP11 promotes IFNAR1 ubiquitination and protects β-TrCP from ubiquitin-proteasome degradation.
Fig. 6: Rucaparib enhances cellular antiviral activity by stablizing IFNAR1.
Fig. 7: Rucaparib enhances host antiviral response in vivo.

Data availability

All data generated or analysed during this study are included in Figs. 17 and Supplementary Figs. 18. Uncropped images of all gels and blots can be found in Supplementary Fig. 9. The data that support the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank S. Y. Fuchs at the University of Pennsylvania for valuable discussions, and E. Y. Chinn for the critical reading of this manuscript. We also thank X. Zhu for technical support. This work was supported by the National Natural Science Foundation of China (31570865 and 31770177 for H.Z., and 31501139 for T.G.), and the program of 1000 Young Talents (2014).

Author information

H.Z. conceived the study. H.Z., T.G., S.X., and C.D. designed the experiments. T.G., Y.Z., L.Q. and J.L. performed most of the experiments and analysed the data. Y.Y., Y.M. and Q.F. assisted with the RNAi screening, transfection and lentivirus experiments, and tissue processing; K.X. assisted with the PCR analyses; X.C. and L.Z. assisted with the mouse experiments, tissue processing and analyses; L.J. assisted with the RT-qPCR; H.Z supervised the project; H.Z. and T.G. wrote the manuscript.

Correspondence to Chunsheng Dong or Sidong Xiong or Hui Zheng.

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