The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP.
Human cytomegalovirus (HCMV) inhibits MHC class I antigen presentation by a sequential multistep process involving a family of unique short (US) region-encoded glycoproteins. US3 retains class I molecules, whereas US2 and US11 mediate the cytosolic degradation of heavy chains by the proteosomes. In US6-transfected cells, however, intracellular transport of class I molecules is impaired because of defective peptide translocation by transporters associated with antigen processing (TAP). Peptide transport is restored in HCMV mutants lacking US6. In contrast to the cytosolic herpes simplex virus protein ICP47, US6 interacts with TAP inside the endoplasmic reticulum lumen, as shown by US6 derivatives lacking the transmembrane and cytoplasmic domains and by the observation that US6 does not prevent peptides from binding to TAP. Thus, HCMV targets TAP for immune escape by a molecular mechanism different from that of herpes simplex virus.
Ahn
K
K
The R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121, USA.
Gruhler
A
A
Galocha
B
B
Jones
T R
TR
Wiertz
E J
EJ
Ploegh
H L
HL
Peterson
P A
PA
Yang
Y
Y
Früh
K
K
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D001692:Biological Transport / Q000276:immunology; D003587:Cytomegalovirus / Q000737:chemistry*; D015536:Down-Regulation / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000502:physiology* / Q000821:virology; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014764:Viral Proteins / Q000494:pharmacology*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D016601:RNA-Binding Proteins; C073119:TAP1 protein, human; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C040495:glycoprotein B, Simplexvirus