Human cytomegalovirus gene products US3 and US6 down-regulate trophoblast class I MHC molecules.
The epidemiological correlation between human CMV (HCMV) infection and spontaneous fetal loss has been suggested, but the underlying mechanism is not well understood. Fetal cytotrophoblasts, which are in direct contact with the maternal immune system in the uterus during pregnancy, do not express HLA-A and HLA-B, but express the nonclassical class I HLA-G and HLA-C. It has been shown that both HLA-G and HLA-C are capable of inhibiting NK-mediated cell lysis. In our present study, using human trophoblast cell lines as well as other cell lines stably transfected with the human class I genes, we have demonstrated that HCMV US3 and US6 down-regulate the cell-surface expression of both HLA-G and HLA-C by two different mechanisms. HCMV US3 physically associates with both trophoblast class I MHC species, retaining them in the endoplasmic reticulum. In contrast, HCMV US6 inhibits peptide transport by TAP and thus specifically the intracellular trafficking of class I molecules. Therefore, these findings suggest for the first time a possible molecular mechanism underlying HCMV-related spontaneous pregnancy loss.
Jun
Y
Y
Graduate School of Biotechnology, Korea University, Seoul, Korea.
Kim
E
E
Jin
M
M
Sung
H C
HC
Han
H
H
Geraghty
D E
DE
Ahn
K
K
D016475:3T3 Cells; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001692:Biological Transport / Q000235:genetics / Q000276:immunology; D002822:Choriocarcinoma; D003587:Cytomegalovirus / Q000235:genetics* / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D006023:Glycoproteins; D006680:HLA Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015236:HLA-C Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008565:Membrane Proteins; D051379:Mice; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D014162:Transfection; D014327:Trophoblasts / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006023:Glycoproteins; D006680:HLA Antigens; D015236:HLA-C Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D010455:Peptides; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C095111:US3 protein, cytomegalovirus; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1