The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor (original) (raw)

Nature volume 456, pages 658–662 (2008)Cite this article

Abstract

Mammalian Toll-like receptors (TLRs) 3, 7, 8 and 9 initiate immune responses to infection by recognizing microbial nucleic acids1,2; however, these responses come at the cost of potential autoimmunity owing to inappropriate recognition of self nucleic acids3. The localization of TLR9 and TLR7 to intracellular compartments seems to have a role in facilitating responses to viral nucleic acids while maintaining tolerance to self nucleic acids, yet the cell biology regulating the transport and localization of these receptors remains poorly understood4,5,6. Here we define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. Notably, although both the full-length and cleaved forms of TLR9 are capable of binding ligand, only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids.

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Acknowledgements

We thank members of the Barton and Vance laboratories for discussions, S. Akira for providing TLR knockout mice, and R. Vance and R. Medzhitov for advice. We acknowledge the CHPS Imaging Core and P. Herzmark for assistance with microscopy. This work was supported by a Novel Research Grant from The Lupus Research Institute (G.M.B.), the Hellman Faculty Fund (G.M.B.), and NIH grants HL67204 (H.A.C.), CA009179 (S.E.E.) and AI072429 (G.M.B.).

Author Contributions S.E.E. and G.M.B. planned experiments and wrote the manuscript. S.E.E., B.L.L., L.L. and K.E.W. performed the experiments. G.-P.S. and H.A.C. contributed reagents. All authors read and commented on the manuscript.

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Authors and Affiliations

  1. Division of Immunology & Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, 405 Life Sciences Addition, Berkeley, California 94720-3200, USA,
    Sarah E. Ewald, Bettina L. Lee, Laura Lau, Katherine E. Wickliffe & Gregory M. Barton
  2. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, NRB-7, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA,
    Guo-Ping Shi
  3. Department of Medicine, and The Cardiovascular Research Institute, University of California, San Francisco, Box 0111, San Francisco, California 94143, USA,
    Harold A. Chapman

Authors

  1. Sarah E. Ewald
  2. Bettina L. Lee
  3. Laura Lau
  4. Katherine E. Wickliffe
  5. Guo-Ping Shi
  6. Harold A. Chapman
  7. Gregory M. Barton

Corresponding author

Correspondence toGregory M. Barton.

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Ewald, S., Lee, B., Lau, L. et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.Nature 456, 658–662 (2008). https://doi.org/10.1038/nature07405

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Editorial Summary

Autoimmunity: TLR9 activation

The role of the Toll-like receptors TLR9 and TLR7 in mediating autoimmune disease to self nucleic acid is now well appreciated, yet the mechanisms preventing rampant autoimmunity remain largely unknown. Here Ewald et al. define the route by which TLR9 and TLR7 exit the endoplasmic reticulum and travel to endolysosomes in mouse macrophages and dendritic cells. TLR9 activation is shown to require proteolytic cleavage in the endolysosome. This may be a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids.