Several of today's cancer treatments are based on the immune system's capacity to detect and destroy cells expressing neoantigens on major histocompatibility class-I molecules (MHC-I). Despite this, we still do not know the cell biology behind how antigenic peptide substrates (APSs) for the MHC-I pathway are produced. Indeed, there are few research fields with so many divergent views as the one concerning the source of APSs. This is quite remarkable considering their fundamental role in the immune systems' capacity to detect and destroy virus-infected or transformed cells. A better understanding of the processes generating APSs and how these are regulated will shed light on the evolution of self-recognition and provide new targets for therapeutic intervention. We discuss the search for the elusive source of MHC-I peptides and highlight the cell biology that is still missing to explain how they are synthesised and where they come from.

• MeSH
• antigeny * MeSH
• histokompatibilita - antigeny třídy I * MeSH
• lidé MeSH
• peptidy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antigeny * MeSH
• histokompatibilita - antigeny třídy I * MeSH
• peptidy MeSH

Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine-alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.

• MeSH
• alanin MeSH
• fosfoproteiny MeSH
• glycin MeSH
• infekce virem Epsteina-Barrové * MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• nukleolin MeSH
• peptidy genetika   MeSH
• proteinové agregáty MeSH
• proteiny vázající RNA metabolismus   MeSH
• virus Epsteinův-Barrové - jaderné antigeny metabolismus   MeSH
• virus Epsteinův-Barrové * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alanin MeSH
• fosfoproteiny MeSH
• glycin MeSH
• messenger RNA MeSH
• peptidy MeSH
• proteinové agregáty MeSH
• proteiny vázající RNA MeSH
• virus Epsteinův-Barrové - jaderné antigeny MeSH

The field of mRNA translation has witnessed an impressive expansion in the last decade. The once standard model of translation initiation has undergone, and is still undergoing, a major overhaul, partly due to more recent technical advancements detailing, for example, initiation at non-AUG codons. However, some of the pioneering works in this area have come from immunology and more precisely from the field of antigen presentation to the major histocompatibility class I (MHC-I) pathway. Despite early innovative studies from the lab of Nilabh Shastri demonstrating alternative mRNA translation initiation as a source for MHC-I peptide substrates, the mRNA translation field did not include these into their models. It was not until the introduction of the ribo-sequence technique that the extent of non-canonical translation initiation became widely acknowledged. The detection of peptides on MHC-I molecules by CD8 + T cells is extremely sensitive, making this a superior model system for studying alternative mRNA translation initiation from specific mRNAs. In view of this, we give a brief history on alternative initiation from an immunology perspective and its fundamental role in allowing the immune system to distinguish self from non-self and at the same time pay tribute to the works of Nilabh Shastri.

• Klíčová slova
• Antigen presentation, MHC class I pathway, mRNA translation initiation,
• MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• histokompatibilita - antigeny třídy I genetika   imunologie   MeSH
• lidé MeSH
• messenger RNA genetika   imunologie   MeSH
• peptidy genetika   imunologie   MeSH
• prezentace antigenu genetika   imunologie   MeSH
• proteosyntéza genetika   imunologie   MeSH
• receptory pro aktivovanou kinasu C genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• histokompatibilita - antigeny třídy I MeSH
• messenger RNA MeSH
• peptide I MeSH Prohlížeč
• peptidy MeSH
• receptory pro aktivovanou kinasu C MeSH

Peptides presented on major histocompatibility (MHC) class I molecules form an essential part of the immune system's capacity to detect virus-infected or transformed cells. Earlier works have shown that pioneer translation peptides (PTPs) for the MHC class I pathway are as efficiently produced from introns as from exons, or from mRNAs targeted for the nonsense-mediated decay pathway. The production of PTPs is a target for viral immune evasion but the underlying molecular mechanisms that govern this non-canonical translation are unknown. Here, we have used different approaches to show how events taking place on the nascent transcript control the synthesis of PTPs and full-length proteins. By controlling the subcellular interaction between the G-quadruplex structure (G4) of a gly-ala encoding mRNA and nucleolin (NCL) and by interfering with mRNA maturation using multiple approaches, we demonstrate that antigenic peptides derive from a nuclear non-canonical translation event that is independently regulated from the synthesis of full-length proteins. Moreover, we show that G4 are exploited to control mRNA localization and translation by distinguishable mechanisms that are targets for viral immune evasion.

• MeSH
• antigeny genetika   imunologie   MeSH
• buněčné jádro genetika   imunologie   MeSH
• G-kvadruplexy MeSH
• histokompatibilita - antigeny třídy I genetika   imunologie   MeSH
• imunitní únik genetika   imunologie   MeSH
• lidé MeSH
• messenger RNA genetika   imunologie   MeSH
• nonsense mediated mRNA decay genetika   imunologie   MeSH
• peptidy genetika   imunologie   MeSH
• proteosyntéza genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny MeSH
• histokompatibilita - antigeny třídy I MeSH
• messenger RNA MeSH
• peptidy MeSH

Cellular immune reactions against non-self-epitopes require activation of cytotoxic CD8+ T-cells via cross-presentation of MHC class I-restricted peptides by professional antigen presenting cells (pAPCs), with the consequent detection and elimination of cells expressing the same antigens via the endogenous (direct) pathway. The source of peptides for the endogenous pathway is constituted of alternative mRNA translation products; however, it is still unclear which source of peptides is used for cross-presentation. Furthermore, the presentation of non-canonical translation products, produced during a non-conventional translation event, on class I molecules of tumor cells has been reported but how these peptides are generated, presented to pAPCs, and their capacity to stimulate CD8+ T cells is still not known. Here, we report that pioneer translation peptides (PTPs) derived from intron or exon pre-mRNAs can serve as tumor-associated antigens (TA-PTPs) and are delivered from the producing tumor cells to pAPCs via exosomes where they are processed by the cytosolic pathway. Injection of TA-PTPs and tumor-derived exosomes efficiently induce CD8+ T-cell proliferation and prevent tumor growth in mice. Our results show that TA-PTPs represent an efficient source of antigenic peptides for CD8+ T cell activation and that full-length proteins are not required for cross-presentation. These findings can have interesting implications for generating tolerance and for designing vectors to generate vaccines.

• Klíčová slova
• Exosomes, MHC-I antigen cross presentation, pioneer translation products, tumor rejection, vaccines,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-to-date account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.

• MeSH
• alternativní sestřih MeSH
• antigeny genetika   metabolismus   MeSH
• histokompatibilita - antigeny třídy I metabolismus   MeSH
• lidé MeSH
• nepřímá aktivace MeSH
• peptidy genetika   metabolismus   MeSH
• prezentace antigenu MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antigeny MeSH
• histokompatibilita - antigeny třídy I MeSH
• peptidy MeSH

The notion that alternative peptide substrates can be processed and presented to the MHC class I pathway has opened for new aspects on how the immune system detects infected or damaged cells. Recent works show that antigenic peptides are derived from intron sequences in pre-mRNAs target for the nonsense-mediated degradation pathway. Introns are spliced out co-transcriptionally suggesting that such pioneer translation products (PTPs) are synthesized on the nascent RNAs in the nuclear compartment to ensure that the first peptides to emerge from an mRNA are destined for the class I pathway. This illustrates an independent translation event during mRNA maturation that give rise to specific peptide products with a specific function in the immune system. The characterization of the translation apparatus responsible for PTP synthesis will pave the way for understanding how PTP production is regulated in different tissues under different conditions and will help designing new vaccine strategies.

• Klíčová slova
• Alternative mRNA translation products, MHC class I antigen presentation,
• MeSH
• buněčné jádro genetika   imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• cytosol imunologie   metabolismus   MeSH
• dendritické buňky cytologie   imunologie   metabolismus   MeSH
• fagozomy genetika   imunologie   MeSH
• histokompatibilita - antigeny třídy I genetika   imunologie   MeSH
• introny MeSH
• lidé MeSH
• peptidy genetika   imunologie   MeSH
• prekurzory RNA genetika   imunologie   MeSH
• prezentace antigenu genetika   MeSH
• proteasomový endopeptidasový komplex genetika   imunologie   MeSH
• proteosyntéza imunologie   MeSH
• sestřih RNA imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• histokompatibilita - antigeny třídy I MeSH
• peptidy MeSH
• prekurzory RNA MeSH
• proteasomový endopeptidasový komplex MeSH