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Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination

Abstract

Dendritic cells have a unique function in the immune response owing to their ability to stimulate immunologically naive T lymphocytes1. In response to microbial and inflammatory stimuli, dendritic cells enhance their capacity for antigen presentation by a process of terminal differentiation, termed maturation2,3. The conversion of immature to mature dendritic cells is accompanied by a marked cellular reorganization, including the redistribution of major histocompatibility complex class II molecules (MHC II) from late endosomal and lysosomal compartments to the plasma membrane4,5,6,7 and the downregulation of some forms of endocytosis, which has been thought to slow the clearance of MHC II from the surface8,9,10,11. The relative extent to which these or other mechanisms contribute to the regulation of surface MHC II remains unclear, however. Here we find that the MHC II β-chain cytoplasmic tail is ubiquitinated in mouse immature dendritic cells. Although only partly required for the sequestration of MHC II in multivesicular bodies, this modification is essential for endocytosis. Notably, ubiquitination of MHC II ceased upon maturation, resulting in the accumulation of MHC II at the cell surface. Dendritic cells thus exhibit a unique ability to regulate MHC II surface expression by selectively controlling MHC II ubiquitination.

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Figure 1: MHC class II molecules are ubiquitinated in dendritic cells.
Figure 2: Differential localization and endocytosis of wild-type MHC II versus the ubiquitin-deficient MHC IIβ(K>R) mutant.
Figure 3: Lysosomal degradation and Ii chain association of ubiquitinated and non-ubiquitinated MHC II in BMDCs.
Figure 4: Loss of MHC II ubiquitination in mature dendritic cells and its role in regulating endocytosis.

References

  1. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998)

    ADS  CAS  Article  Google Scholar 

  2. Mellman, I. & Steinman, R. M. Dendritic cells: specialized and regulated antigen processing machines. Cell 106, 255–258 (2001)

    CAS  Article  Google Scholar 

  3. Reis e Sousa, C. Dendritic cells in a mature age. Nature Rev. Immunol. 6, 476–483 (2006)

    CAS  Article  Google Scholar 

  4. Trombetta, E. S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo.. Annu. Rev. Immunol. 23, 975–1028 (2005)

    CAS  Article  Google Scholar 

  5. Chow, A., Toomre, D., Garrett, W. & Mellman, I. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418, 988–994 (2002)

    ADS  CAS  Article  Google Scholar 

  6. Turley, S. J. et al. Transport of peptide-MHC class II complexes in developing dendritic cells. Science 288, 522–527 (2000)

    CAS  Article  Google Scholar 

  7. Boes, M. et al. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418, 983–988 (2002)

    ADS  CAS  Article  Google Scholar 

  8. Garrett, W. S. et al. Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102, 325–334 (2000)

    CAS  Article  Google Scholar 

  9. Wilson, N. S., El-Sukkari, D. & Villadangos, J. A. Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis. Blood 103, 2187–2195 (2004)

    CAS  Article  Google Scholar 

  10. West, M. A., Prescott, A. R., Eskelinen, E. L., Ridley, A. J. & Watts, C. Rac is required for constitutive macropinocytosis by dendritic cells but does not control its downregulation. Curr. Biol. 10, 839–848 (2000)

    CAS  Article  Google Scholar 

  11. Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 182, 389–400 (1995)

    CAS  Article  Google Scholar 

  12. Hicke, L. & Dunn, R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu. Rev. Cell Dev. Biol. 19, 141–172 (2003)

    CAS  Article  Google Scholar 

  13. Raiborg, C., Rusten, T. E. & Stenmark, H. Protein sorting into multivesicular endosomes. Curr. Opin. Cell Biol. 15, 446–455 (2003)

    CAS  Article  Google Scholar 

  14. Marmor, M. D. & Yarden, Y. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 23, 2057–2070 (2004)

    CAS  Article  Google Scholar 

  15. Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893–905 (2002)

    CAS  Article  Google Scholar 

  16. Ohmura-Hoshino, M. et al. Inhibition of MHC class II expression and immune responses by c-MIR. J. Immunol. 177, 341–354 (2006)

    CAS  Article  Google Scholar 

  17. Pinet, V., Vergelli, M., Martin, R., Bakke, O. & Long, E. O. Antigen presentation mediated by recycling of surface HLA-DR molecules. Nature 375, 603–606 (1995)

    ADS  CAS  Article  Google Scholar 

  18. Cella, M., Engering, A., Pinet, V., Pieters, J. & Lanzavecchia, A. Inflammatory stimuli induce accumulation of MHC class II complexes on dendritic cells. Nature 388, 782–787 (1997)

    ADS  CAS  Article  Google Scholar 

  19. Zhong, G., Romagnoli, P. & Germain, R. N. Related leucine-based cytoplasmic targeting signals in invariant chain and major histocompatibility complex class II molecules control endocytic presentation of distinct determinants in a single protein. J. Exp. Med. 185, 429–438 (1997)

    CAS  Article  Google Scholar 

  20. Pathak, S. S., Lich, J. D. & Blum, J. S. Cutting edge: editing of recycling class II:peptide complexes by HLA-DM. J. Immunol. 167, 632–635 (2001)

    CAS  Article  Google Scholar 

  21. Salamero, J., Humbert, M., Cosson, P. & Davoust, J. Mouse B lymphocyte specific endocytosis and recycling of MHC class II molecules. EMBO J. 9, 3489–3496 (1990)

    CAS  Article  Google Scholar 

  22. Colledge, L., Bennett, C. L., Reay, P. A. & Blackburn, C. C. Rapid constitutive generation of a specific peptide-MHC class II complex from intact exogenous protein in immature murine dendritic cells. Eur. J. Immunol. 32, 3246–3255 (2002)

    CAS  Article  Google Scholar 

  23. Mosesson, Y. et al. Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation. J. Biol. Chem. 278, 21323–21326 (2003)

    CAS  Article  Google Scholar 

  24. Miyake, S., Lupher, M. L., Druker, B. & Band, H. The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor α. Proc. Natl Acad. Sci. USA 95, 7927–7932 (1998)

    ADS  CAS  Article  Google Scholar 

  25. Haglund, K. et al. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nature Cell Biol. 5, 461–466 (2003)

    CAS  Article  Google Scholar 

  26. Beck, T., Schmidt, A. & Hall, M. N. Starvation induces vacuolar targeting and degradation of the tryptophan permease in yeast. J. Cell Biol. 146, 1227–1238 (1999)

    CAS  Article  Google Scholar 

  27. Helliwell, S. B., Losko, S. & Kaiser, C. A. Components of a ubiquitin ligase complex specify polyubiquitination and intracellular trafficking of the general amino acid permease. J. Cell Biol. 153, 649–662 (2001)

    CAS  Article  Google Scholar 

  28. Villadangos, J. A., Riese, R. J., Peters, C., Chapman, H. A. & Ploegh, H. L. Degradation of mouse invariant chain: roles of cathepsins S and D and the influence of major histocompatibility complex polymorphism. J. Exp. Med. 186, 549–560 (1997)

    CAS  Article  Google Scholar 

  29. Matza, D., Kerem, A. & Shachar, I. Invariant chain, a chain of command. Trends Immunol. 24, 264–268 (2003)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank members of the Mellarren laboratory group for advice and support. J.-S.S. is a Fellow of the Jane Coffin Childs Foundation. I.M. is an Affiliate Member of the Ludwig Institute for Cancer Research. This work was supported by the NIH and by the Ludwig Institute for Cancer Research.

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Correspondence to Ira Mellman.

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Shin, JS., Ebersold, M., Pypaert, M. et al. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444, 115–118 (2006). https://doi.org/10.1038/nature05261

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