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:

UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes

Nature volume 452, pages 234–238 (2008)Cite this article

Abstract

Signalling by means of toll-like receptors (TLRs) is essential for the development of innate and adaptive immune responses1,2,3. UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER)4,5,6. Here we show that the function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes. In dendritic cells of 3d mice, which express an UNC93B1 missense mutant (H412R) incapable of TLR binding, neither TLR7 nor TLR9 exits the ER. Furthermore, the trafficking and signalling defects of the nucleotide-sensing TLRs in 3d dendritic cells are corrected by expression of wild-type UNC93B1. However, UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs. To our knowledge, UNC93B1 is the first protein to be identified as a molecule specifically involved in trafficking of nucleotide-sensing TLRs. By inhibiting the interaction between UNC93B1 and TLRs it should be possible to achieve specific regulation of the nucleotide-sensing TLRs without compromising signalling via the cell-surface-disposed TLRs.

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: TLR7 and TLR9 fail to translocate to endolysosomes in 3d cells.
Figure 2: Expression of wild-type UNC93B1 in 3d cells rescues defects of TLR trafficking and signalling.
Figure 3: Wild-type UNC93B1 delivers the nucleotide-sensing TLRs to endolysosomes.
Figure 4: UNC93B1 is dispensable for ligand recognition and signal initiation by TLR.

Similar content being viewed by others

References

  1. Janeway, C. A. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002)

    Article  CAS  Google Scholar 

  2. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003)

    Article  CAS  Google Scholar 

  3. Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006)

    Article  CAS  Google Scholar 

  4. Tabeta, K. et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nature Immunol. 7, 156–164 (2006)

    Article  CAS  Google Scholar 

  5. Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006)

    Article  ADS  CAS  Google Scholar 

  6. Brinkmann, M. M. et al. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J. Cell Biol. 177, 265–275 (2007)

    Article  CAS  Google Scholar 

  7. Latz, E. et al. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2–CD14 complex in a process that is distinct from the initiation of signal transduction. J. Biol. Chem. 277, 47834–47843 (2002)

    Article  CAS  Google Scholar 

  8. Ahmad-Nejad, P. et al. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 32, 1958–1968 (2002)

    Article  CAS  Google Scholar 

  9. Nishiya, T. & DeFranco, A. L. Ligand-regulated chimeric receptor approach reveals distinctive subcellular localization and signaling properties of the Toll-like receptors. J. Biol. Chem. 279, 19008–19017 (2004)

    Article  CAS  Google Scholar 

  10. Matsumoto, M. et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J. Immunol. 171, 3154–3162 (2003)

    Article  CAS  Google Scholar 

  11. Nishiya, T., Kajita, E., Miwa, S. & Defranco, A. L. TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J. Biol. Chem. 280, 37107–37117 (2005)

    Article  CAS  Google Scholar 

  12. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190–198 (2004)

    Article  CAS  Google Scholar 

  13. Leifer, C. A. et al. TLR9 is localized in the endoplasmic reticulum prior to stimulation. J. Immunol. 173, 1179–1183 (2004)

    Article  CAS  Google Scholar 

  14. Barton, G. M., Kagan, J. C. & Medzhitov, R. Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nature Immunol. 7, 49–56 (2006)

    Article  CAS  Google Scholar 

  15. Conley, M. E. Immunodeficiency: UNC-93B gets a toll call. Trends Immunol. 28, 99–101 (2007)

    Article  CAS  Google Scholar 

  16. Janssen, E. et al. Efficient T cell activation via a Toll-Interleukin 1 Receptor-independent pathway. Immunity 24, 787–799 (2006)

    Article  CAS  Google Scholar 

  17. Shaner, N. C. et al. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nature Biotechnol. 22, 1567–1572 (2004)

    Article  CAS  Google Scholar 

  18. Kovacsovics-Bankowski, M., Clark, K., Benacerraf, B. & Rock, K. L. Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages. Proc. Natl Acad. Sci. USA 90, 4942–4946 (1993)

    Article  ADS  CAS  Google Scholar 

  19. Juschke, C., Ferring, D., Jansen, R. P. & Seedorf, M. A novel transport pathway for a yeast plasma membrane protein encoded by a localized mRNA. Curr. Biol. 14, 406–411 (2004)

    Article  CAS  Google Scholar 

  20. Franz, A., Maass, K. & Seedorf, M. A complex peptide-sorting signal, but no mRNA signal, is required for the Sec-independent transport of Ist2 from the yeast ER to the plasma membrane. FEBS Lett. 581, 401–405 (2007)

    Article  CAS  Google Scholar 

  21. Schnare, M., Holt, A. C., Takeda, K., Akira, S. & Medzhitov, R. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr. Biol. 10, 1139–1142 (2000)

    Article  CAS  Google Scholar 

  22. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003)

    Article  ADS  CAS  Google Scholar 

  23. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003)

    Article  ADS  CAS  Google Scholar 

  24. Juschke, C., Wachter, A., Schwappach, B. & Seedorf, M. SEC18/NSF-independent, protein-sorting pathway from the yeast cortical ER to the plasma membrane. J. Cell Biol. 169, 613–622 (2005)

    Article  Google Scholar 

Download references

Acknowledgements

We are grateful to J. Vyas for CD63–cherry-expressing lentivirus, B. Beutler for 3d mice, and T. Nishiya for TLR–YFP constructs. We also thank M. Seedorf for sharing his insights on the Ist2p sequence tag and for providing us with Ist2p tag constructs. We thank B. Mueller and J. Loureiro for discussions and critical reading of the manuscript. This study was supported by grants from the NIH (to H.L.P.), the German Research Council (to M.M.B.) and fonds de recherche en sante du Quebec (to M.-E.P.).

Author information

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,

    You-Me Kim, Melanie M. Brinkmann, Marie-Eve Paquet & Hidde L. Ploegh

Authors
  1. You-Me Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melanie M. Brinkmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Eve Paquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hidde L. Ploegh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to You-Me Kim or Hidde L. Ploegh.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-8 with Legends. (PDF 1531 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, YM., Brinkmann, M., Paquet, ME. et al. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452, 234–238 (2008). https://doi.org/10.1038/nature06726

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06726

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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