Regulation of protein translation through mRNA structure influences MHC class I loading and T cell recognition.
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 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.
Tellam
Judy
J
Australian Center for Vaccine Development and Tumor Immunology, Division of Infectious Diseases and Immunology, Clive Berghofer Cancer Research Center, Queensland Institute of Medical Research, Brisbane 4006 QLD, Australia.
Smith
Corey
C
Rist
Michael
M
Webb
Natasha
N
Cooper
Leanne
L
Vuocolo
Tony
T
Connolly
Geoff
G
Tscharke
David C
DC
Devoy
Michael P
MP
Khanna
Rajiv
R
D017951:Antigen Presentation / Q000276:immunology*; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D003062:Codon / Q000235:genetics; D000939:Epitopes / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D016376:Oligonucleotides, Antisense; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D011687:Purines; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry* / Q000235:genetics
D003062:Codon; D000939:Epitopes; D019309:Epstein-Barr Virus Nuclear Antigens; D015395:Histocompatibility Antigens Class I; D016376:Oligonucleotides, Antisense; D011687:Purines; D012333:RNA, Messenger