MHC-I peptidome analysis of human foreskin fibroblasts

Ribosome profiling (Ribo-seq) recently revealed the expression of thousands of short open reading frames (sORFs) in eukaryotic cells. They encode for a class of instable peptides, which evade experimental validation by whole-proteome mass spectrometry. Here, we show that computational elimination of experimental noise from Ribo-seq data unravels fundamental new aspects of sORF biology. Based on the revised annotation of cellular sORFs, we show that sORF-derived peptides are efficiently incorporated into MHC-I. sORFs thus encode a novel class of stress-responsive antigens in human cells. Our findings have broad implications on the functional, regulatory and immunogenic role of sORFs in fundamental cellular processes like infection and cancer.