[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
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.

  • Letter
  • Published:

TRIM5 is an innate immune sensor for the retrovirus capsid lattice

Nature volume 472, pages 361–365 (2011)Cite this article

Subjects

Abstract

TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm1,2. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice3,4 and several reports indicate that TRIM5 has a role in signal transduction5,6,7, but the precise mechanism of restriction is unknown8. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13–UEV1A (also known as UBE2N–UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFκB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13–UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-κB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13–UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

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

Figure 1: TRIM5 promotes innate immune signalling.
Figure 2: The TAK1 kinase complex interacts biochemically and functionally with TRIM5.
Figure 3: TRIM5 acts with UBC13–UEV1A to synthesize free K63-linked Ub chains that activate TAK1.
Figure 4: Retrovirus capsid sensing by TRIM5.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Sayah, D. M., Sokolskaja, E., Berthoux, L. & Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430, 569–573 (2004)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  3. Sebastian, S. & Luban, J. TRIM5α selectively binds a restriction-sensitive retroviral capsid. Retrovirology 2, 40 (2005)

    Article  Google Scholar 

  4. Stremlau, M. et al. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor. Proc. Natl Acad. Sci. USA 103, 5514–5519 (2006)

    Article  ADS  CAS  Google Scholar 

  5. Berthoux, L. et al. As2O3 enhances retroviral reverse transcription and counteracts Ref1 antiviral activity. J. Virol. 77, 3167–3180 (2003)

    Article  CAS  Google Scholar 

  6. Shi, M. et al. TRIM30α negatively regulates TLR-mediated NF-κΒ activation by targeting TAB2 and TAB3 for degradation. Nature Immunol. 9, 369–377 (2008)

    Article  ADS  CAS  Google Scholar 

  7. Tareen, S. U. & Emerman, M. Human Trim5α has additional activities that are uncoupled from retroviral capsid recognition. Virology 409, 113–120 (2011)

    Article  CAS  Google Scholar 

  8. Luban, J. & Cyclophilin, A. TRIM5, and resistance to human immunodeficiency virus type 1 infection. J. Virol. 81, 1054–1061 (2007)

    Article  CAS  Google Scholar 

  9. Panne, D., Maniatis, T. & Harrison, S. C. An atomic model of the interferon-β enhanceosome. Cell 129, 1111–1123 (2007)

    Article  CAS  Google Scholar 

  10. Ishii, K. J., Koyama, S., Nakagawa, A., Coban, C. & Akira, S. Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe 3, 352–363 (2008)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  12. Kornbluth, R. S., Oh, P. S., Munis, J. R., Cleveland, P. H. & Richman, D. D. Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro . J. Exp. Med. 169, 1137–1151 (1989)

    Article  CAS  Google Scholar 

  13. Neagu, M. R. et al. Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. J. Clin. Invest. 119, 3035–3047 (2009)

    Article  CAS  Google Scholar 

  14. Roe, T., Reynolds, T. C., Yu, G. & Brown, P. O. Integration of murine leukemia virus DNA depends on mitosis. EMBO J. 12, 2099–2108 (1993)

    Article  CAS  Google Scholar 

  15. Berthoux, L., Sebastian, S., Sokolskaja, E. & Luban, J. Cyclophilin A is required for TRIM5α-mediated resistance to HIV-1 in Old World monkey cells. Proc. Natl Acad. Sci. USA 102, 14849–14853 (2005)

    Article  ADS  CAS  Google Scholar 

  16. Zeng, W. et al. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141, 315–330 (2010)

    Article  CAS  Google Scholar 

  17. Langelier, C. R. et al. Biochemical characterization of a recombinant TRIM5α protein that restricts human immunodeficiency virus type 1 replication. J. Virol. 82, 11682–11694 (2008)

    Article  CAS  Google Scholar 

  18. Yin, Q., Lamothe, B., Darnay, B. G. & Wu, H. Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry 48, 10558–10567 (2009)

    Article  CAS  Google Scholar 

  19. Sokolskaja, E., Berthoux, L. & Luban, J. Cyclophilin A and TRIM5α independently regulate human immunodeficiency virus type 1 infectivity in human cells. J. Virol. 80, 2855–2862 (2006)

    Article  CAS  Google Scholar 

  20. Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee-Kirsch, M. A. & Lieberman, J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nature Immunol. 11, 1005–1013 (2010)

    Article  CAS  Google Scholar 

  21. Perron, M. J. et al. TRIM5α mediates the postentry block to N-tropic murine leukemia viruses in human cells. Proc. Natl Acad. Sci. USA 101, 11827–11832 (2004)

    Article  ADS  CAS  Google Scholar 

  22. Ulm, J. W., Perron, M., Sodroski, J. & Mulligan, R. C. Complex determinants within the Moloney murine leukemia virus capsid modulate susceptibility of the virus to Fv1 and Ref1-mediated restriction. Virology 363, 245–255 (2007)

    Article  CAS  Google Scholar 

  23. Pornillos, O. et al. X-ray structures of the hexameric building block of the HIV capsid. Cell 137, 1282–1292 (2009)

    Article  Google Scholar 

  24. Ganser, B. K., Li, S., Klishko, V. Y., Finch, J. T. & Sundquist, W. I. Assembly and analysis of conical models for the HIV-1 core. Science 283, 80–83 (1999)

    Article  ADS  CAS  Google Scholar 

  25. Ganser-Pornillos, B. K. et al. Hexagonal assembly of a restricting TRIM5α protein. Proc. Natl Acad. Sci. USA 108, 534–539 (2011)

    Article  ADS  CAS  Google Scholar 

  26. Medzhitov, R. & Littman, D. HIV immunology needs a new direction. Nature 455, 591 (2008)

    Article  ADS  CAS  Google Scholar 

  27. Pornillos, O., Ganser-Pornillos, B. K. & Yeager, M. Atomic-level modelling of the HIV capsid. Nature 469, 424–427 (2011)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Baltimore, M. J. Birrer, J. Brojatsch, A. Cimarelli, A. DeIaco, S. Elledge, M. Emerman, W. Ferlin, D. Garcin, S. Ghosh, O. Haller, T. Hatziioannou, J. Hiscott, A. Iwasaki, D. Kolakofsky, M. Kosco-Vilbois, H. Malik, R. Medzhitov, M. R. Neagu, G. Napolitani, P. Palese, D. Pinschewer, O. Pornillos, L. Roux, O. Schwartz, M. Strubin, V. Studer, W. Sundquist, G. Towers, D. Trono, J. Tschopp, M. Yeager, M. Zufferey, and the Functional Genomics Center (Zürich), for ideas, technical assistance, and reagents. This work was supported by NIH grant RO1AI59159 to J.L., NIH grant R21AI087467 to W.M., Swiss National Science Foundation grant 3100A0-128655 to J.L. and 3100A0-122342 to M.G. and UZH Forschungskredit 54041402 to S.Z.

Author information

Authors and Affiliations

  1. Department of Microbiology and Molecular Medicine, University of Geneva, Geneva CH-1211, Switzerland

    Thomas Pertel, Stéphane Hausmann, Jessica Guerra, Josefina Lascano, Christian Reinhard, Federico A. Santoni, Caterina Strambio-De-Castillia, Massimo Pizzato & Jeremy Luban

  2. Department of Biochemistry, University of Zurich, Zurich CH-8057, Switzerland

    Damien Morger, Sara Züger & Markus G. Grütter

  3. Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, 06536, Connecticut, USA

    Pradeep D. Uchil & Walther Mothes

  4. Novimmune SA, Geneva CH-1228, Switzerland

    Laurence Chatel

  5. Institut Pasteur, Inserm U818, Paris 75724, France

    Aurélie Bisiaux & Matthew L. Albert

Authors
  1. Thomas Pertel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stéphane Hausmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Damien Morger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Züger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jessica Guerra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Josefina Lascano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christian Reinhard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Federico A. Santoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pradeep D. Uchil
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laurence Chatel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aurélie Bisiaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Matthew L. Albert
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Caterina Strambio-De-Castillia
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Walther Mothes
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Massimo Pizzato
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Markus G. Grütter
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jeremy Luban
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.P., S.H., J.G., C.R., C.S., M.P., W.M., M.G.G. and J.L. designed the experiments; T.P., S.H., D.M., S.Z., J.G., J.La., C.R., F.A.S., M.P., A.B., P.D.U. and L.C. performed the experiments. All authors contributed to the assembly and writing of the manuscript.

Corresponding author

Correspondence to Jeremy Luban.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, additional references and Supplementary Tables 1-3. (PDF 553 kb)

Supplementary Figures

This file contains Supplementary Figures 1-12 with legends. (PDF 1521 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pertel, T., Hausmann, S., Morger, D. et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472, 361–365 (2011). https://doi.org/10.1038/nature09976

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09976

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