Global proteogenomic analysis of human MHC I peptides derived from noncanonical reading frames

Using highthroughput mass spectrometry, we probed the sixreadingframe translation of human B cells’ transcriptome. We report that about 10% of MHC Iassociated peptides (MAPs) derive from noncanonical reading frames. These socalled cryptic MAPs originate from allegedly non- coding genomic sequences and from outofframe translation. Their biogenesis and properties differ in many ways from those of conventional MAPs. Thus, cryptic MAPs come from very short proteins with atypical Ctermini, and they are coded by transcripts bearing long UTRs selectively enriched in destabilizing elements. Cryptic MAPs increase the complexity of the immunopeptidome and represent an heretofore unexploited source of potential tumorspecific epitopes. In a more general context, the features of cryptic MAPs suggest that mRNA instability is instrumental in the biogenesis of MAPs. Associated RNA-seq accession: GSE67174 .