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Effects of messenger RNA structure and other translational control mechanisms on major histocompatibility complex‐I mediated antigen presentation

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Effective T‐cell surveillance of antigen‐presenting cells is dependent on the expression of an array of antigenic peptides bound to major histocompatibility complex (MHC) class I (MHC‐I) or class II (MHC‐II) molecules. Pathogens co‐evolving with their hosts exploit crucial translational regulatory mechanisms in order to evade host immune recognition and thereby sustain their infection. Evasion strategies that downregulate viral protein synthesis and thereby restrict antigen presentation to cytotoxic T‐cells through the endogenous MHC‐I pathway have been implicated in the pathogenesis of viral‐associated malignancies. An understanding of the mechanisms by which messenger RNA (mRNA) structure modulates both viral mRNA translation and the antigen processing machinery to escape immune surveillance, will stimulate the development of alternative therapeutic strategies focused on RNA‐directed drugs designed to enhance immune responses against infected cells. In this review, we discuss regulatory aspects of the MHC‐I pathway and summarize current knowledge of the role attributed by mRNA structure and other translational regulatory mechanisms in immune evasion. In particular we highlight the impact of recently identified G‐quadruplex structures within virally encoded transcripts as unique regulatory signals for translational control and antigen presentation. WIREs RNA 2015, 6:157–171. doi: 10.1002/wrna.1262 This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems Translation > Translation Regulation
The MHC class I antigen presentation pathway. Once transcribed, viral mRNAs are translated into proteins that constitute the pool of MHC‐I restricted epitopes resulting from proteasomal degradation of nascent proteins and DRiPs. Degraded peptides are translocated into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) where chaperones facilitate their binding to newly synthesized MHC‐I molecules for vesicular migration through the golgi to the cell surface. Cytotoxic T lymphocytes recognize viral antigenic peptides and initiate an immune response. Viruses that evade the immune system have evolved to interfere with key steps of the MHC‐I presentation pathway. Strategies that downregulate viral protein synthesis through translational control mechanisms can lead to immune evasion and subsequent latent infection.
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RNA structures within viral mRNAs are targets for translational control and antigen presentation. (a) Destabilization or stabilization of G‐quadruplexes using antisense oligonucleotides or small molecule G‐quadruplex ligands (Pyridostatin), respectively, stimulates or inhibits the synthesis of the EBV‐genome maintenance protein, EBNA1, and subsequent generation and presentation of MHC‐I‐restricted antigenic peptides. (b) The formation of mRNA secondary structures resulting from the presence of LNA downstream slippery sequences control ribosomal frameshift and the synthesis of alternative antigenic peptides. (c) Structure of a small molecule that binds and stabilizes the stem‐loop structure controlling the HIV‐1 gag‐pol programmed ribosomal frameshift. Stabilization of the RNA secondary structure enhances frameshifting in cells.
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Schematic view of translational control mechanisms that regulate viral protein synthesis and antigen presentation. (a) Canonical translation of a viral mRNA is initiated at the AUG codon and leads to the synthesis of a viral protein that is the source of MHC‐I‐restricted antigenic peptides. (b) Formation of G‐quadruplex motifs within the ORF of gammaherpesviruses impede translation through ribosome stalling/dissociation and inhibit the presentation of MHC‐I‐restricted antigenic peptides. (c) RNA structures within the 5′‐untranslated region of enteroviruses control replication and translation of the viral genome by recruiting cellular and viral proteins. The ribonucleoprotein complex modulates the synthesis of viral proteins. (d) The translation of alternative reading frames induced by non‐AUG translation initiation or RNA structure mediated programmed frameshifting, is the source of alternative antigenic peptides that diversify the pool of MHC‐I‐restricted epitopes.
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mRNA structures that affect MHC‐I mediated antigen presentation. (a) RNA G‐quadruplexes within gammaherpes viral ORFs negatively impact antigen presentation. G‐quadruplex structures are formed by guanine‐rich sequences and are stabilized by the stacking of guanine‐tetrads that are formed by the coplanar arrangement of four guanines interacting by Hoogsteen hydrogen‐bonding and stabilized by monovalent cations (usually K+). (b) Cloverleaf structures identified in the 5'‐untranslated regions of poliovirus. Cloverleaf structures in enteroviruses control the replication and translation of the viral genomes through the formation of ribonucleoprotein complexes. (c) HIV‐1 programmed ribosomal frameshift signal secondary structure. The formation of the stem‐loop structure downstream of a slippery sequence leads to the translocating ribosome to stall and induce a ‐1 frameshift that insures the synthesis of pol and gag which are encoded by the same ORF.
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RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems

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