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.

The carboxypeptidase ACE shapes the MHC class I peptide repertoire

Abstract

The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8+ T cell–mediated adaptive immune responses. Aminopeptidases have been linked to the editing of peptides for MHC class I loading, but carboxy-terminal editing is thought to be due to proteasome cleavage. By analysis of wild-type mice and mice genetically deficient in or overexpressing the dipeptidase angiotensin-converting enzyme (ACE), we have now identified ACE as having a physiological role in the processing of peptides for MHC class I. ACE edited the carboxyl terminus of proteasome-produced MHC class I peptides. The lack of ACE exposed new antigens but also abrogated some self antigens. ACE had substantial effects on the surface expression of MHC class I in a haplotype-dependent manner. We propose a revised model of peptide processing for MHC class I by introducing carboxypeptidase activity into the process.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: ACE is upregulated during APC maturation.
Figure 2: The effect of ACE on surface expression of MHC class I.
Figure 3: ACE-deficient cells have normal MHC class I–peptide stability but more peptide supply.
Figure 4: The effect of ACE on the CD8+ T cell repertoire.
Figure 5: The effect of ACE in editing self antigens.
Figure 6: The effect of ACE on the presentation of viral antigens.
Figure 7: ACE works as a carboxyl dipeptidase on proteasome products.

References

  1. Jensen, P.E. Recent advances in antigen processing and presentation. Nat. Immunol. 8, 1041–1048 (2007).

    Article  CAS  Google Scholar 

  2. Wearsch, P.A. & Cresswell, P. The quality control of MHC class I peptide loading. Curr. Opin. Cell Biol. 20, 624–631 (2008).

    Article  CAS  Google Scholar 

  3. Purcell, A.W. & Elliott, T. Molecular machinations of the MHC-I peptide loading complex. Curr. Opin. Immunol. 20, 75–81 (2008).

    Article  CAS  Google Scholar 

  4. Rock, K.L., York, I.A. & Goldberg, A.L. Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat. Immunol. 5, 670–677 (2004).

    Article  CAS  Google Scholar 

  5. Rammensee, H.G., Friede, T. & Stevanoviíc, S. MHC ligands and peptide motifs: first listing. Immunogenetics 41, 178–228 (1995).

    Article  CAS  Google Scholar 

  6. Saveanu, L., Carroll, O., Hassainya, Y. & van Endert, P. Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation. Immunol. Rev. 207, 42–59 (2005).

    Article  CAS  Google Scholar 

  7. Serwold, T., Gonzalez, F., Kim, J., Jacob, R. & Shastri, N. ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419, 480–483 (2002).

    Article  CAS  Google Scholar 

  8. Saric, T. et al. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat. Immunol. 3, 1169–1176 (2002).

    Article  CAS  Google Scholar 

  9. Mo, X.Y., Cascio, P., Lemerise, K., Goldberg, A.L. & Rock, K. Distinct proteolytic processes generate the C and N termini of MHC class I-binding peptides. J. Immunol. 163, 5851–5859 (1999).

    CAS  PubMed  Google Scholar 

  10. Rammensee, H.G. Peptides made to order. Immunity 25, 693–695 (2006).

    Article  CAS  Google Scholar 

  11. Kessler, J.H. et al. Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nat. Immunol. 12, 45–53 (2011).

    Article  CAS  Google Scholar 

  12. Hooper, N.M. Angiotensin converting enzyme: implications from molecular biology for its physiological functions. Int. J. Biochem. 23, 641–647 (1991).

    Article  CAS  Google Scholar 

  13. Corvol, P., Williams, T.A. & Soubrier, F. Peptidyl dipeptidase A: angiotensin I-converting enzyme. Methods Enzymol. 248, 283–305 (1995).

    Article  CAS  Google Scholar 

  14. Shen, X.Z., Lukacher, A.E., Billet, S., Williams, I.R. & Bernstein, K.E. Expression of angiotensin-converting enzyme changes major histocompatibility complex class I peptide presentation by modifying C termini of peptide precursors. J. Biol. Chem. 283, 9957–9965 (2008).

    Article  CAS  Google Scholar 

  15. Harmer, D., Gilbert, M., Borman, R. & Clark, K.L. Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett. 532, 107–110 (2002).

    Article  CAS  Google Scholar 

  16. Danilov, S.M. et al. Angiotensin-converting enzyme (CD143) is abundantly expressed by dendritic cells and discriminates human monocyte-derived dendritic cells from acute myeloid leukemia-derived dendritic cells. Exp. Hematol. 31, 1301–1309 (2003).

    Article  CAS  Google Scholar 

  17. Saijonmaa, O., Nyman, T. & Fyhrquist, F. Atorvastatin inhibits angiotensin-converting enzyme induction in differentiating human macrophages. Am. J. Physiol. Heart Circ. Physiol. 292, H1917–H1921 (2007).

    Article  CAS  Google Scholar 

  18. Eisenlohr, L.C., Bacik, I., Bennink, J.R., Bernstein, K. & Yewdell, J.W. Expression of a membrane protease enhances presentation of endogenous antigens to MHC class I-restricted T lymphocytes. Cell 71, 963–972 (1992).

    Article  CAS  Google Scholar 

  19. Kozlowski, S. et al. Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules. J. Exp. Med. 175, 1417–1422 (1992).

    Article  CAS  Google Scholar 

  20. Strehl, B. et al. Interferon-γ, the functional plasticity of the ubiquitin-proteasome system, and MHC class I antigen processing. Immunol. Rev. 207, 19–30 (2005).

    Article  CAS  Google Scholar 

  21. Esther, C.R. et al. Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab. Invest. 74, 953–965 (1996).

    CAS  PubMed  Google Scholar 

  22. Shen, X.Z. et al. Mice with enhanced macrophage angiotensin-converting enzyme are resistant to melanoma. Am. J. Pathol. 170, 2122–2134 (2007).

    Article  CAS  Google Scholar 

  23. Hammer, G.E., Gonzalez, F., James, E., Nolla, H. & Shastri, N. In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nat. Immunol. 8, 101–108 (2007).

    Article  CAS  Google Scholar 

  24. Simpson, E., Scott, D. & Chandler, P. The male-specific histocompatibility antigen, H-Y: a history of transplantation, immune response genes, sex determination and expression cloning. Annu. Rev. Immunol. 15, 39–61 (1997).

    Article  CAS  Google Scholar 

  25. Greenfield, A. et al. An H-YDb epitope is encoded by a novel mouse Y chromosome gene. Nat. Genet. 14, 474–478 (1996).

    Article  CAS  Google Scholar 

  26. Kemball, C.C. et al. Late priming and variability of epitope-specific CD8+ T cell responses during a persistent virus infection. J. Immunol. 174, 7950–7960 (2005).

    Article  CAS  Google Scholar 

  27. Andrews, N.P., Pack, C.D. & Lukacher, A.E. Generation of antiviral major histocompatibility complex class I-restricted T cells in the absence of CD8 coreceptors. J. Virol. 82, 4697–4705 (2008).

    Article  CAS  Google Scholar 

  28. Cushman, D.W., Cheung, H.S., Sabo, E.F. & Ondetti, M.A. Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. Biochemistry 16, 5484–5491 (1977).

    Article  CAS  Google Scholar 

  29. Kanaseki, T., Blanchard, N., Hammer, G.E., Gonzalez, F. & Shastri, N. ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum. Immunity 25, 795–806 (2006).

    Article  CAS  Google Scholar 

  30. Fuchs, S. et al. Role of the N-terminal catalytic domain of angiotensin-converting enzyme investigated by targeted inactivation in mice. J. Biol. Chem. 279, 15946–15953 (2004).

    Article  CAS  Google Scholar 

  31. Craiu, A., Akopian, T., Goldberg, A. & Rock, K.L. Two distinct proteolytic processes in the generation of a major histocompatibility complex class I-presented peptide. Proc. Natl. Acad. Sci. USA 94, 10850–10855 (1997).

    Article  CAS  Google Scholar 

  32. Stoltze, L. et al. Generation of the vesicular stomatitis virus nucleoprotein cytotoxic T lymphocyte epitope requires proteasome-dependent and -independent proteolytic activities. Eur. J. Immunol. 28, 4029–4036 (1998).

    Article  CAS  Google Scholar 

  33. Kunisawa, J. & Shastri, N. The group II chaperonin TRiC protects proteolytic intermediates from degradation in the MHC class I antigen processing pathway. Mol. Cell 12, 565–576 (2003).

    Article  CAS  Google Scholar 

  34. Skidgel, R.A. & Erdös, E.G. Angiotensin I converting enzyme. Adv. Exp. Med. Biol. 247A, 25–28 (1989).

    Article  CAS  Google Scholar 

  35. Hemming, M.L. & Selkoe, D.J. Amyloid β-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J. Biol. Chem. 280, 37644–37650 (2005).

    Article  CAS  Google Scholar 

  36. Chang, S.C., Momburg, F., Bhutani, N. & Goldberg, A.L. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc. Natl. Acad. Sci. USA 102, 17107–17112 (2005).

    Article  CAS  Google Scholar 

  37. Androlewicz, M.J. & Cresswell, P. How selective is the transporter associated with antigen processing? Immunity 5, 1–5 (1996).

    Article  CAS  Google Scholar 

  38. Koopmann, J.O., Post, M., Neefjes, J.J., Hämmerling, G.J. & Momburg, F. Translocation of long peptides by transporters associated with antigen processing (TAP). Eur. J. Immunol. 26, 1720–1728 (1996).

    Article  CAS  Google Scholar 

  39. Schumacher, T.N. et al. Peptide length and sequence specificity of the mouse TAP1/TAP2 translocator. J. Exp. Med. 179, 533–540 (1994).

    Article  CAS  Google Scholar 

  40. Momburg, F. et al. Selectivity of MHC-encoded peptide transporters from human, mouse and rat. Nature 367, 648–651 (1994).

    Article  CAS  Google Scholar 

  41. Lauterbach, H., Gruber, A., Ried, C., Cheminay, C. & Brocker, T. Insufficient APC capacities of dendritic cells in gene gun-mediated DNA vaccination. J. Immunol. 176, 4600–4607 (2006).

    Article  CAS  Google Scholar 

  42. Cole, J. et al. Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice. J. Clin. Invest. 106, 1391–1398 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Fuchs and E. Bernstein for vector construction; D. Roopenian and G. Christianson (Jackson Laboratories) for the minor histocompatibility CTL clones and assistance with cultures; G. Khitrov for assistance in liquid chromatography–mass spectrometry; G.E. Hammer for technical assistance with immunization; Q. Xu for assistance with RT-PCR; S. McLachlan (Cedars-Sinai Medical Center) for A20 cells; C. Ried (University of Munich) for Cd11c promoter DNA; R. Germain (US National Institutes of Health) for antibody 25D-1.16; R. Ahmed (Emory University) for L. monocytogenes strain EGD; and B. Taylor for administrative support. Supported by the US National Institutes of Health (R01 DK 039777 to K.E.B. and R01 CA 71971 to A.E.L.).

Author information

Authors and Affiliations

Authors

Contributions

X.Z.S., study conception and experimental design; X.Z.S. and S.B., experimental input, with assistance from C.L. (RT-PCR), D.O.-D. (L. monocytogenes infection) and X.C. (minigene construction); A.E.L., intellectual advice and reagents for polyomavirus experiments; K.E.B., intellectual advice and project coordination; X.Z.S. and K.E.B., manuscript authorship.

Corresponding author

Correspondence to Kenneth E Bernstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Table 1 (PDF 752 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shen, X., Billet, S., Lin, C. et al. The carboxypeptidase ACE shapes the MHC class I peptide repertoire. Nat Immunol 12, 1078–1085 (2011). https://doi.org/10.1038/ni.2107

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2107

This article is cited by

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