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:

Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21

Nature Immunology volume 14, pages 327–336 (2013)Cite this article

Subjects

Abstract

During pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we found that recognition of intracellular antibodies by TRIM21 activated immune signaling. TRIM21 catalyzed the formation of Lys63 (K63)-linked ubiquitin chains and stimulated the transcription factor pathways of NF-κB, AP-1, IRF3, IRF5 and IRF7. Activation resulted in the production of proinflammatory cytokines, modulation of natural killer stress ligands and induction of an antiviral state. Intracellular antibody signaling was abrogated by genetic deletion of TRIM21 and was restored by ectopic expression of TRIM21. The sensing of antibodies by TRIM21 was stimulated after infection by DNA or RNA nonenveloped viruses or intracellular bacteria. Thus, the antibody-TRIM21 detection system provides potent, comprehensive activation of the innate immune system independently of known pattern-recognition receptors.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: TRIM21 senses intracellular antibody-bound virus.
Figure 2: The TRIM21 RING domain synthesizes K63-linked ubiquitin chains.
Figure 3: TRIM21 signaling is dependent on TAK1 and stimulates the NF-κB, AP-1 and IRF pathways.
Figure 4: TRIM21 signaling initiates the production of proinflammatory cytokines.
Figure 5: Detection of intracellular antibody-bound pathogens promotes an antiviral state.
Figure 6: TRIM21 promotes NF-κB signaling in response to viral and bacterial pathogens.
Figure 7: TRIM21 signaling is independent of TLR, FcR, ADIN and PAMPs.
Figure 8: TRIM21 mediates an inflammatory response in primary human and mouse cells.

Similar content being viewed by others

References

  1. Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    CAS  PubMed  Google Scholar 

  4. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Bianchi, M.E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81, 1–5 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Mallery, D.L. et al. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc. Natl. Acad. Sci. USA 107, 19985–19990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. James, L.C., Keeble, A.H., Khan, Z., Rhodes, D.A. & Trowsdale, J. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc. Natl. Acad. Sci. USA 104, 6200–6205 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hauler, F., Mallery, D.L., McEwan, W.A., Bidgood, S.R. & James, L.C. AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization. Proc. Natl. Acad. Sci. USA 109, 19733–19738 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McEwan, W.A., Mallery, D.L., Rhodes, D.A., Trowsdale, J. & James, L.C. Intracellular antibody-mediated immunity and the role of TRIM21. Bioessays 33, 803–809 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. McEwan, W.A. et al. Regulation of virus neutralization and the persistent fraction by TRIM21. J. Virol. 86, 8482–8491 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Stremlau, M. et al. The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature 427, 848–853 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Pertel, T. et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472, 361–365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Keeble, A.H., Khan, Z., Forster, A. & James, L.C. TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved. Proc. Natl. Acad. Sci. USA 105, 6045–6050 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wertz, I.E. & Dixit, V.M. Signaling to NF-κB: regulation by ubiquitination. Cold Spring Harb. Perspect. Biol. 2, a003350 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Xia, Z.P. et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 461, 114–119 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ea, C.K., Deng, L., Xia, Z.P., Pineda, G. & Chen, Z.J. Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 22, 245–257 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Wu, C.J., Conze, D.B., Li, T., Srinivasula, S.M. & Ashwell, J.D. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation. Nat. Cell Biol. 8, 398–406 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Yang, K. et al. TRIM21 is essential to sustain IFN regulatory factor 3 activation during antiviral response. J. Immunol. 182, 3782–3792 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Kong, H.J. et al. Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J. Immunol. 179, 26–30 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Young, J.A. et al. Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production. J. Biol. Chem. 286, 6521–6531 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Higgs, R. et al. Self protection from anti-viral responses–Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS ONE 5, e11776 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Higgs, R. et al. The E3 ubiquitin ligase Ro52 negatively regulates IFN-β production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J. Immunol. 181, 1780–1786 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Champsaur, M. & Lanier, L.L. Effect of NKG2D ligand expression on host immune responses. Immunol. Rev. 235, 267–285 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ben-Israel, H. & Kleinberger, T. Adenovirus and cell cycle control. Front. Biosci. 7, d1369–d1395 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Morse, L., Chen, D., Franklin, D., Xiong, Y. & Chen-Kiang, S. Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18INK4c and IL-6. Immunity 6, 47–56 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Schreiber, M. et al. Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev. 13, 607–619 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liebermann, D.A. & Hoffman, B. Myeloid differentiation (MyD)/growth arrest DNA damage (GADD) genes in tumor suppression, immunity and inflammation. Leukemia 16, 527–541 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Smith, E.C., Popa, A., Chang, A., Masante, C. & Dutch, R.E. Viral entry mechanisms: the increasing diversity of paramyxovirus entry. FEBS J. 276, 7217–7227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Beuzón, C.R., Salcedo, S.P. & Holden, D.W. Growth and killing of a Salmonella enterica serovar Typhimurium sifA mutant strain in the cytosol of different host cell lines. Microbiology 148, 2705–2715 (2002).

    Article  PubMed  Google Scholar 

  30. Birmingham, C.L. & Brumell, J.H. Autophagy recognizes intracellular Salmonella enterica serovar Typhimurium in damaged vacuoles. Autophagy 2, 156–158 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Beuzón, C.R. et al. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. EMBO J. 19, 3235–3249 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Petrovska, L. et al. Salmonella enterica serovar Typhimurium interaction with dendritic cells: impact of the sifA gene. Cell Microbiol. 6, 1071–1084 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Schmitz, H., Wigand, R. & Heinrich, W. Worldwide epidemiology of human adenovirus infections. Am. J. Epidemiol. 117, 455–466 (1983).

    Article  CAS  PubMed  Google Scholar 

  34. Yoshimi, R. et al. Gene disruption study reveals a nonredundant role for TRIM21/Ro52 in NF-κB-dependent cytokine expression in fibroblasts. J. Immunol. 182, 7527–7538 (2009).

    CAS  PubMed  Google Scholar 

  35. Fuchs, R. & Blaas, D. Uncoating of human rhinoviruses. Rev. Med. Virol. 20, 281–297 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Negishi, H. et al. Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses. Nat. Immunol. 13, 659–666 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Koshiba, R. et al. Regulation of cooperative function of the Il12b enhancer and promoter by the interferon regulatory factors 3 and 5. Biochem. Biophys. Res. Commun. 430, 95–100 (2012).

    Article  PubMed  Google Scholar 

  38. Chatterji, U. et al. Trim5α accelerates degradation of cytosolic capsid associated with productive HIV-1 entry. J. Biol. Chem. 281, 37025–37033 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Diaz-Griffero, F. et al. Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5. Virology 349, 300–315 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Barouch, D.H. Novel adenovirus vector-based vaccines for HIV-1. Curr Opin HIV AIDS 5, 386–390 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Cheng, C. et al. Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination. PLoS ONE 7, e33969 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Muruve, D.A. The innate immune response to adenovirus vectors. Hum. Gene Ther. 15, 1157–1166 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Peeples (Nationwide Children's Hospital) for RSV; and D. Brown (University of Cambridge) for FCV. Supported by the Medical Research Council (U105181010), the European Research Council (281627-IAI) and the Frank Edward Elmore Fund of the University of Cambridge School of Clinical Medicine (J.C.H.T.).

Author information

Authors and Affiliations

  1. Division of Protein and Nucleic Acid Chemistry, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    William A McEwan, Jerry C H Tam, Ruth E Watkinson, Susanna R Bidgood, Donna L Mallery & Leo C James

Authors
  1. William A McEwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerry C H Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruth E Watkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susanna R Bidgood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donna L Mallery
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leo C James
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.A.M. and L.C.J. initiated the study; W.A.M., J.C.H.T. and L.C.J. wrote the manuscript; and all authors conceived of and did experiments, analyzed data, edited the manuscript and prepared figures.

Corresponding authors

Correspondence to William A McEwan or Leo C James.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 2747 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

McEwan, W., Tam, J., Watkinson, R. et al. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol 14, 327–336 (2013). https://doi.org/10.1038/ni.2548

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2548

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