Folding of Matrix Metalloproteinase-2 Prevents Endogenous Generation of MHC Class-I Restricted Epitope |
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| Authors: | Virginie Renaud Emmanuelle Godefroy Pierre Larrieu Fabrice Fleury Francine Jotereau Yannick Guilloux |
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| Affiliation: | 1. Institut National de la Santé et de la Recherche Médicale, UMR 892, Nantes, France.; 2. Cancer Institute, New York University School of Medicine, New York, New York, United States of America.; 3. Faculté des Sciences et Techniques de Nantes, Nantes, France.; 4. Centre nationale de la Recherche Scientifique Unité de Biotechnologie, Biocatalyse et Biorégulation, Nantes, France.;Karolinska Institutet, Sweden |
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| Abstract: | BackgroundWe previously demonstrated that the matrix metalloproteinase-2 (MMP-2) contained an antigenic peptide recognized by a CD8 T cell clone in the HLA-A*0201 context. The presentation of this peptide on class I molecules by human melanoma cells required a cross-presentation mechanism. Surprisingly, the classical endogenous processing pathway did not process this MMP-2 epitope.Methodology/Principal FindingsBy PCR directed mutagenesis we showed that disruption of a single disulfide bond induced MMP-2 epitope presentation. By Pulse-Chase experiment, we demonstrated that disulfide bonds stabilized MMP-2 and impeded its degradation. Finally, using drugs, we documented that mutated MMP-2 epitope presentation used the proteasome and retrotranslocation complex.Conclusions/SignificanceThese data appear crucial to us since they established the existence of a new inhibitory mechanism for the generation of a T cell epitope. In spite of MMP-2 classified as a self-antigen, the fact that cross-presentation is the only way to present this MMP-2 epitope underlines the importance to target this type of antigen in immunotherapy protocols. |
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