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Regulation of protein translation through mRNAstructure influences MHC class I loading andT cell recognition

Tellam, Judy; Smith, Corey; Rist, Michael; Webb, Natasha; Cooper, Leanne; Vuocolo, Tony; Connolly, Geoff; Tscharke, David; Devoy, Michael; Khanna, Rajiv

Description

Many viruses avoid immune surveillance during latent infection through reduction in the synthesis of virally encoded proteins. Although antigen presentation critically depends on the level of viral protein synthesis, the precise mechanism used to regulate the generation of antigenic peptide precursors remains elusive. Here, we demonstrate that a purine overloaded virally encoded mRNA lacking secondary structure significantly impacts the efficiency of protein translation and prevents endogenous...[Show more]

dc.contributor.authorTellam, Judy
dc.contributor.authorSmith, Corey
dc.contributor.authorRist, Michael
dc.contributor.authorWebb, Natasha
dc.contributor.authorCooper, Leanne
dc.contributor.authorVuocolo, Tony
dc.contributor.authorConnolly, Geoff
dc.contributor.authorTscharke, David
dc.contributor.authorDevoy, Michael
dc.contributor.authorKhanna, Rajiv
dc.date.accessioned2015-12-10T21:56:28Z
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/1885/39438
dc.description.abstractMany viruses avoid immune surveillance during latent infection through reduction in the synthesis of virally encoded proteins. Although antigen presentation critically depends on the level of viral protein synthesis, the precise mechanism used to regulate the generation of antigenic peptide precursors remains elusive. Here, we demonstrate that a purine overloaded virally encoded mRNA lacking secondary structure significantly impacts the efficiency of protein translation and prevents endogenous antigen presentation. Reducing this purine bias through the generation of constructs expressing codon-modified sequences, while maintaining the encoded protein sequence, increased the stem-loop structure of the corresponding mRNA and dramatically enhanced self-synthesis of the viral protein. As a consequence, a higher number of HLA-peptide complexes were detected on the surface of cells expressing this viral protein. Furthermore, these cells were more efficiently recognized by virus-specific T cells compared with those expressing the same antigen expressed by a purine-biased mRNA. These findings delineate a mechanism by which viruses regulate self-synthesis of proteins and offer an effective strategy to evade CD8+ T cell-mediated immune regulation.
dc.publisherNational Academy of Sciences (USA)
dc.sourcePNAS - Proceedings of the National Academy of Sciences of the United States of America
dc.subjectKeywords: Epstein Barr virus antigen; amino acid sequence; antigen presentation; article; CD8+ T lymphocyte; controlled study; human; human cell; immunoregulation; in vitro study; major histocompatibility complex; priority journal; protein expression; protein synth Antigen processing; EBV-encoded nuclear antigen 1; Immune evasion; Protein synthesis
dc.titleRegulation of protein translation through mRNAstructure influences MHC class I loading andT cell recognition
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume105
dc.date.issued2008
local.identifier.absfor110799 - Immunology not elsewhere classified
local.identifier.absfor110704 - Cellular Immunology
local.identifier.ariespublicationu4325460xPUB177
local.type.statusPublished Version
local.contributor.affiliationTellam, Judy, Queensland Institute of Medical Research
local.contributor.affiliationSmith, Corey, Queensland Institute of Medical Research
local.contributor.affiliationRist, Michael, Queensland Institute of Medical Research
local.contributor.affiliationWebb, Natasha, University of Queensland
local.contributor.affiliationCooper, Leanne, University of Queensland
local.contributor.affiliationVuocolo, Tony, CSIRO Livestock
local.contributor.affiliationConnolly, Geoff, Queensland Institute of Medical Research
local.contributor.affiliationTscharke, David, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationDevoy, Michael, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationKhanna, Rajiv, University of Queensland
local.description.embargo2037-12-31
local.bibliographicCitation.issue27
local.bibliographicCitation.startpage9319
local.bibliographicCitation.lastpage9324
local.identifier.doi10.1073/pnas.0801968105
dc.date.updated2015-12-09T07:38:02Z
local.identifier.scopusID2-s2.0-48249117542
local.identifier.thomsonID000257645400035
CollectionsANU Research Publications

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