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.
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.
"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). "
[Show abstract][Hide abstract] ABSTRACT: The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function.
[Show abstract][Hide abstract] ABSTRACT: Classical MHC class I molecules open a window into the cell by presenting intracellular peptides (pMHC I) on the surface. The peptides are used for immune surveillance by circulating CD8+ T and NK cells to detect and eliminate infected or tumor cells. Not surprisingly, viruses and tumor cells have evolved immune evasion mechanisms to keep the window shades down and the cytotoxic cells oblivious to their presence. Here, we review counter mechanisms that nevertheless allow the immune system to detect and eliminate cells unable to properly process antigenic peptides in the endoplasmic reticulum.
Current opinion in immunology 02/2014; 26C(1):123-127. DOI:10.1016/j.coi.2013.11.006 · 7.48 Impact Factor
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