The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation.
In its attempt to evade cytotoxic T cell recognition, human cytomegalovirus encodes several genes that target MHC class I molecules at different points in their assembly pathway. We show here that the human cytomegalovirus US6 gene encodes a 22-kDa glycoprotein that binds the transporter-associated with antigen processing (TAP)/class I complex and inhibits translocation of peptide from the cytosol to the endoplasmic reticulum. Major histocompatibility complex class I molecules are therefore unable to load TAP-dependent peptides, resulting in the retention of MHC class I molecules in the endoplasmic reticulum, with a consequent reduction in class I at the cell surface. Interferon-gamma treatment of US6 transfected cells overcomes this inhibition of peptide translocation and restores class I at the cell surface to wild type levels. The functional consequence of TAP inhibition is that US6 transfected cells are unable to present endogenous antigen to cytotoxic T lymphocytes and are therefore resistant to cytotoxic T lymphocyte lysis.
Lehner
P J
PJ
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA.
Karttunen
J T
JT
Wilkinson
G W
GW
Cresswell
P
P
D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002461:Cell Line, Transformed; D003587:Cytomegalovirus / Q000276:immunology*; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; D007371:Interferon-gamma