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Global proteogenomic analysis of human MHC class I-associated peptides derived from non-canonical reading frames

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms10238

2041-1723

Céline M. Laumont, Tariq Daouda, Jean‐Philippe Laverdure, Éric Bonneil, Olivier Caron-Lizotte, Marie‐Pierre Hardy, Diana Paola Granados, Chantal Durette, Sébastien Lemieux, Pierre Thibault, Claude Perreault,

Glycosylation and Glycoproteins Research

Abstract In view of recent reports documenting pervasive translation outside of canonical protein-coding sequences, we wished to determine the proportion of major histocompatibility complex (MHC) class I-associated peptides (MAPs) derived from non-canonical reading frames. Here we perform proteogenomic analyses of MAPs eluted from human B cells using high-throughput mass spectrometry to probe the six-frame translation of the B-cell transcriptome. We report that ∼10% of MAPs originate from allegedly noncoding genomic sequences or exonic out-of-frame translation. The biogenesis and properties of these ‘cryptic MAPs’ differ from those of conventional MAPs. Cryptic MAPs come from very short proteins with atypical C termini, and are coded by transcripts bearing long 3′UTRs enriched in destabilizing elements. Relative to conventional MAPs, cryptic MAPs display different MHC class I-binding preferences and harbour more genomic polymorphisms, some of which are immunogenic. Cryptic MAPs increase the complexity of the MAP repertoire and enhance the scope of CD8 T-cell immunosurveillance.