Role for ribosomal quality control in sampling proteins for MHC class I-mediated antigen presentation

Mammalian cells present a fingerprint of their proteome to the adaptive immune system through the display of endogenous peptides on MHC-I complexes. MHC-I peptides originate from protein degradation by the proteasome, suggesting that efficiently-folding, long-lived proteins could evade monitoring. Here, we investigate the role of the ribosomal quality control (RQC) pathway, responsible for the degradation of nascent chains stalled at the ribosome during translation, in sampling proteins for antigen presentation. We find that degradation and presentation on MHC-I of model proteins encoded by defective mRNAs is independent of their folding potential. Quantitative profiling of MHC-I peptides in wild-type and RQC-deficient cells by mass spectrometry showed that RQC substantially contributes to the composition of the immunopeptidome. Our results not only reveal the role of RQC in sampling proteins that are otherwise difficult to present due to their folding properties, but also identify endogenous substrates of the RQC pathway in human cells.