The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation.
Human cytomegalovirus (HCMV) encodes an endoplasmic reticulum (ER)-resident transmembrane glycoprotein, US10, expressed early in the replicative cycle of HCMV as part of the same cluster that encodes the known immunoevasins US2, US3, US6, and US11. We show that US10 down-regulates cell surface expression of HLA-G, but not that of classical class I MHC molecules. The unique and short cytoplasmic tail of HLA-G (RKKSSD) is essential in its role as a US10 substrate, and a tri-leucine motif in the cytoplasmic tail of US10 is responsible for down-regulation of HLA-G. Both the kinetics of HLA-G degradation and the mechanisms responsible appear to be distinct from those used by the US2 and US11 pathways, suggesting the existence of a third route of protein dislocation from the ER. We show that US10-mediated degradation of HLA-G interferes with HLA-G-mediated NK cell inhibition. Given the role of HLA-G in protecting the fetus from attack by the maternal immune system and in directing the differentiation of human dendritic cells to promote the evolution of regulatory T cells, HCMV likely targets the HLA-G-dependent axis of immune recognition no less efficiently than it interferes with classical class I MHC-restricted antigen presentation.
Park
Boyoun
B
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02115, USA.
Spooner
Eric
E
Houser
Brandy L
BL
Strominger
Jack L
JL
Ploegh
Hidde L
HL
D000595:Amino Acid Sequence; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology* / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D006031:Glycosylation / Q000187:drug effects; D006680:HLA Antigens / Q000276:immunology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; C456062:US10 glycoprotein, Human herpesvirus 5; D014764:Viral Proteins