Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Microbiology volume 4, pages 1872–1884 (2019)Cite this article

Subjects

Matters Arising to this article was published on 24 October 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Data availability

All data generated or analysed during this study are included in Figs. 1–7 and Supplementary Figs. 1–8. 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.

References

  1. Levy, D. E., Kessler, D. S., Pine, R., Reich, N. & Darnell, J. E. Jr. Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 2, 383–393 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. Sadler, A. J. & Williams, B. R. Interferon-inducible antiviral effectors. Nat. Rev. Immunol. 8, 559–568 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Qian, J. et al. Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1. PLoS Pathog. 7, e1002065 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Liu, J. et al. Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell Host Microbe 5, 72–83 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kumar, K. G. et al. SCF(HOS) ubiquitin ligase mediates the ligand-induced down-regulation of the interferon-α receptor. EMBO J. 22, 5480–5490 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Kumar, K. G., Krolewski, J. J. & Fuchs, S. Y. Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. J. Biol. Chem. 279, 46614–46620 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Zheng, H., Qian, J., Varghese, B., Baker, D. P. & Fuchs, S. Ligand-stimulated downregulation of the alpha interferon receptor: role of protein kinase D2. Mol. Cell. Biol. 31, 710–720 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Gibson, B. A. & Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411–424 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Schreiber, V., Dantzer, F., Ame, J. C. & de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 7, 517–528 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Audebert, M., Salles, B. & Calsou, P. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J. Biol. Chem. 279, 55117–55126 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Langelier, M. F., Planck, J. L., Roy, S. & Pascal, J. M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science 336, 728–732 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kraus, W. L. & Lis, J. T. PARP goes transcription. Cell 113, 677–683 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Luo, X. & Kraus, W. L. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 26, 417–432 (2012).

  14. Hassa, P. O. & Hottiger, M. O. The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell. Mol. Life Sci. 59, 1534–1553 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pellegrino, S. & Altmeyer, M. Interplay between ubiquitin, SUMO, and poly(ADP-Ribose) in the cellular response to genotoxic stress. Front. Genet. 7, 63 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Ekblad, T., Camaioni, E., Schuler, H. & Macchiarulo, A. PARP inhibitors: polypharmacology versus selective inhibition. FEBS J. 280, 3563–3575 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Jagtap, P. & Szabo, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat. Rev. Drug Discov. 4, 421–440 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Wahlberg, E. et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat. Biotechnol. 30, 283–288 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Lin, K. Y. & Kraus, W. L. PARP inhibitors for cancer therapy. Cell 169, 183 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Kim, G. et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin. Cancer Res. 21, 4257–4261 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Balasubramaniam, S. et al. FDA approval summary: rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer. Clin. Cancer Res. 23, 7165–7170 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Erener, S. et al. Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-κB target genes. Mol. Cell 46, 200–211 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Verheugd, P. et al. Regulation of NF-κB signalling by the mono-ADP-ribosyltransferase ARTD10. Nat. Commun. 4, 1683 (2013).

    Article  PubMed  CAS  Google Scholar 

  25. Barkauskaite, E., Jankevicius, G. & Ahel, I. Structures and mechanisms of enzymes employed in the synthesis and degradation of PARP-dependent protein ADP-ribosylation. Mol. Cell 58, 935–946 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, Y. et al. PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. Nat. Immunol. 16, 1215–1227 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Todorova, T., Bock, F. J. & Chang, P. PARP13 regulates cellular mRNA post-transcriptionally and functions as a pro-apoptotic factor by destabilizing TRAILR4 transcript. Nat. Commun. 5, 5362 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Zheng, H. et al. A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep. 5, 180–193 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Vyas, S. et al. Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat. Commun. 5, 4426 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Sowa, M. E., Bennett, E. J., Gygi, S. P. & Harper, J. W. Defining the human deubiquitinating enzyme interaction landscape. Cell 138, 389–403 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Otto, H. et al. In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs). BMC Genomics 6, 139 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Kleine, H. et al. Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation. Mol. Cell 32, 57–69 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Iwata, H. et al. PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nat. Commun. 7, 12849 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gagne, J. P. et al. Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes. Nucleic Acids Res. 36, 6959–6976 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pleschke, J. M., Kleczkowska, H. E., Strohm, M. & Althaus, F. R. Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. J. Biol. Chem. 275, 40974–40980 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Rosenthal, F. et al. Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases. Nat. Struct. Mol. Biol. 20, 502–507 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Kalisch, T., Ame, J. C., Dantzer, F. & Schreiber, V. New readers and interpretations of poly(ADP-ribosyl)ation. Trends Biochem. Sci. 37, 381–390 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feijs, K. L., Forst, A. H., Verheugd, P. & Luscher, B. Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation. Nat. Rev. Mol. Cell Biol. 14, 443–451 (2013).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Galan, J. M. & Peter, M. Ubiquitin-dependent degradation of multiple F-box proteins by an autocatalytic mechanism. Proc. Natl Acad. Sci. USA 96, 9124–9129 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhou, P. & Howley, P. M. Ubiquitination and degradation of the substrate recognition subunits of SCF ubiquitin-protein ligases. Mol. Cell 2, 571–580 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Li, Y., Gazdoiu, S., Pan, Z. Q. & Fuchs, S. Y. Stability of homologue of Slimb F-box protein is regulated by availability of its substrate. J. Biol. Chem. 279, 11074–11080 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ghosh, R., Roy, S. & Franco, S. PARP1 depletion induces RIG-I-dependent signaling in human cancer cells. PloS ONE 13, e0194611 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Meyer-Ficca, M. L. et al. Spermatid head elongation with normal nuclear shaping requires ADP-ribosyltransferase PARP11 (ARTD11) in mice. Biol. Reprod. 92, 80 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhang, Y. et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat. Cell Biol. 13, 623–629 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Kang, H. C. et al. Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. Proc. Natl Acad. Sci. USA 108, 14103–14108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fuchs, S. Y., Spiegelman, V. S. & Kumar, K. G. The many faces of β-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer. Oncogene 23, 2028–2036 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors and Affiliations

  1. International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China

    Tingting Guo, Yibo Zuo, Liping Qian, Jin Liu, Yukang Yuan, Kailin Xu, Ying Miao, Qian Feng, Xiangjie Chen, Lincong Jin, Liting Zhang, Chunsheng Dong, Sidong Xiong & Hui Zheng

  2. Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, China

    Tingting Guo, Yibo Zuo, Liping Qian, Jin Liu, Yukang Yuan, Ying Miao, Qian Feng, Xiangjie Chen, Lincong Jin, Liting Zhang, Sidong Xiong & Hui Zheng

Authors
  1. Tingting Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yibo Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liping Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yukang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kailin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qian Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiangjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lincong Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Liting Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Chunsheng Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sidong Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hui Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Chunsheng Dong, Sidong Xiong or Hui Zheng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figures 1–9.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, T., Zuo, Y., Qian, L. et al. ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase β-TrCP. Nat Microbiol 4, 1872–1884 (2019). https://doi.org/10.1038/s41564-019-0428-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41564-019-0428-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing