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Redox regulation of peptide receptivity of major histocompatibility complex class I molecules by ERp57 and tapasin

Nature Immunology volume 8, pages 864–872 (2007)Cite this article

Abstract

The function of the oxidoreductase ERp57 in the major histocompatibility complex (MHC) class I peptide-loading complex has remained elusive. Here we show that in the absence of tapasin, the α2 disulfide bond in the MHC class I peptide-binding groove was rapidly reduced. Covalent sequestration of ERp57 by tapasin was needed to protect the α2 disulfide bond against reduction and thus to maintain the binding groove in a peptide-receptive state. Allelic variations in MHC class I tapasin dependency reflected their susceptibility to reduction of the α2 disulfide bond. In the absence of sequestration, ERp57 acted directly on the α2 disulfide bond. Our work provides insight into how the immune system customizes 'quality control' in the endoplasmic reticulum to fit the needs of antigen presentation.

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Figure 1: Design and characterization of MHC class I expression constructs optimized for redox analysis.
Figure 2: Tapasin Cys95 is required for the maintenance of HLA-B*4402 heavy chains in the fully oxidized state.
Figure 3: The tapasin-independent MHC class I allele HLA-B*4405 is resistant to α2 reduction.
Figure 4: Tapasin Cys95 protects HLA-B*4402 against disulfide exchange with ERp57.
Figure 5: Heavy chain–ERp57 conjugates are associated with CRT.
Figure 6: The formation of the CRT-associated heavy chain–ERp57 conjugate is suppressed by wild-type tapasin but not by the C95A mutant.
Figure 7: Depletion of ERp57 leads to less expression of heavy chain.

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Acknowledgements

We thank C. Mader for expert technical assistance; F. Momburg, N. Garbi and N. Bangia (Roswell Park Cancer Institute) for discussions; and F. Momburg and P. Cresswell (Yale University) for reagents. Supported by the Deutsche Forschungsgemeinschaft (DI 731/2-1) and the European Commission (Marie Curie Excellence Grant).

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Authors and Affiliations

  1. Redox Regulation Research Group, German Cancer Research Center, Heidelberg, D-69120, Germany

    Alexandra Kienast, Marc Preuss, Monique Winkler & Tobias P Dick

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  1. Alexandra Kienast
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  2. Marc Preuss
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Contributions

T.P.D. designed the research, supervised the experiments, analyzed data and wrote the manuscript; A.K. designed experiments, did most experiments, analyzed data and contributed to the writing of the manuscript; M.P. did PDI experiments; and M.W. contributed to ERp57 depletion experiments.

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Correspondence to Tobias P Dick.

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The authors declare no competing financial interests.

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Kienast, A., Preuss, M., Winkler, M. et al. Redox regulation of peptide receptivity of major histocompatibility complex class I molecules by ERp57 and tapasin. Nat Immunol 8, 864–872 (2007). https://doi.org/10.1038/ni1483

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