A single residue exchange within a viral CTL epitope alters proteasome-mediated degradation resulting in lack of antigen presentation.
CTL epitope (KSPWFTTL) encoded by AKV/MCF type of murine leukemia virus (MuLV) differs from the sequence in Friend/Moloney/Rauscher (FMR) type in one residue (RSPWFTTL). CTL experiments indicated defective processing of the FMR peptide in tumor cells. Proteasome-mediated digestion of AKV/MCF-type 26-mer peptides resulted in the early generation and higher levels of epitope-containing fragments than digestion of FMR-type peptides, explained by prominent cleavage next to R in the FMR sequence. The fragments were identified as 10- and 11-mer peptides and were efficiently translocated by TAP. The naturally presented AKV/MCF peptide is the 8-mer, indicating ER peptide trimming. In conclusion, a single residue exchange can cause CTL epitope destruction by specific proteasomal cleavage.
Ossendorp
F
F
Department of Immunohematology, Academic Hospital Leiden, The Netherlands.
Eggers
M
M
Neisig
A
A
Ruppert
T
T
Groettrup
M
M
Sijts
A
A
Mengedë
E
E
Kloetzel
P M
PM
Neefjes
J
J
Koszinowski
U
U
Melief
C
C
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D000957:Antigens, Viral, Tumor / Q000276:immunology* / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000494:pharmacology*; D000939:Epitopes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D009052:Leukemia Virus, Murine / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000494:pharmacology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000957:Antigens, Viral, Tumor; D000939:Epitopes; D006023:Glycoproteins; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex