Post-Endoplasmic Reticulum Rescue of Unstable MHC Class I Requires Proprotein Convertase PC7

作者：Leonhardt Ralf M; Fiegl Dorothee; Rufer Elke; Karger Axel; Bettin Barbara; Knittlert Michael R^*

来源：The Journal of Immunology, 2010, 184(6): 2985-2998.

DOI：10.4049/jimmunol.0900308

The function of the peptide-loading complex (PLC) is to facilitate loading of MHC class I (MHC 1) molecules with antigenic peptides in the endoplasmic reticulum and to drive the selection of these ligands toward a set of high-affinity binders. When the PLC fails to perform properly, as frequently observed in virus-infected or tumor cells, structurally unstable MHC I peptide complexes are generated, which are prone to disintegrate instead of presenting Ags to cytotoxic T cells. In this study we show that a second quality control checkpoint dependent on the serine protease proprotein convertase 7 (PC7) can rescue unstable MHC 1, whereas the related convertase furin is completely dispensable. Cells with a malfunctioning PLC and silenced for PC7 have substantially reduced MHC I surface levels caused by high instability and significantly delayed surface accumulation of these molecules. Instead of acquiring stability along the secretory route, MHC I appears to get largely routed to lysosomes for degradation in these cells. Moreover, mass spectrometry analysis provides evidence that lack of PLC quality control and/or loss of PC7 expression alters the MHC I-presented peptide profile. Finally, using exogenously applied peptide precursors, we show that liberation of MHC I epitopes may directly require PC7. We demonstrate for the first time an important function for PC7 in MHC I-mediated Ag presentation. The Journal of Immunology, 2010, 184: 2985-2998.

• 出版日期2010-3-15