Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway

Cibles Thérapeutiques, Equipe Labellisé la Ligue Contre le Cancer, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 940, Institut de Génétique Moléculaire, Hôpital St. Louis, Université Paris 7, F-75010 Paris, France.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2013; 110(44). DOI: 10.1073/pnas.1309956110
Source: PubMed


The scanning of maturing mRNAs by ribosomes plays a key role in the mRNA quality control process. When ribosomes first engage with the newly synthesized mRNA, and if peptides are produced, is unclear, however. Here we show that ribosomal scanning of prespliced mRNAs occurs in the nuclear compartment, and that this event produces peptide substrates for the MHC class I pathway. Inserting antigenic peptide sequences in introns that are spliced out before the mRNAs exit the nuclear compartment results in an equal amount of antigenic peptide products as when the peptides are encoded from the main open reading frame (ORF). Taken together with the detection of intron-encoded nascent peptides and RPS6/RPL7-carrying complexes in the perinucleolar compartment, these results show that peptides are produced by a translation event occurring before mRNA splicing. This suggests that ribosomes occupy and scan mRNAs early in the mRNA maturation process, and suggests a physiological role for nuclear mRNA translation, and also helps explain how the immune system tolerates peptides derived from tissue-specific mRNA splice variants.

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    • "Peptides encoded in the intron are generated by an unknown mode of translation before pre-mRNA splicing and subsequent mRNA nuclear export. The peptides are presented to the major histocompatibility complex (MHC) I pathway in cells expressing all possible splice variants during T-cell-negative selection, thus preventing autoimmune reactions (Apcher et al., 2013). "
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