Subtle sequence variation among MHC class I locus products greatly influences sensitivity to HCMV US2- and US11-mediated degradation.
Human cytomegalovirus (HCMV) interferes with cellular immune responses by modulating surface expression of MHC class I molecules. Here, we focused on HCMV-encoded unique short (US) 2 and US11, which bind newly synthesized MHC class I heavy chains (HCs) and support their dislocation into the cytosol for subsequent degradation by proteasomes. Not all MHC class I locus products are equally sensitive to this down-modulation. The aim of this study was to identify which domains, and ultimately which residues, are responsible for the resistance or sensitivity of MHC class I molecules to US2- and US11-mediated down-regulation. We show that, besides endoplasmic reticulum-lumenal regions, the C-terminus of class I molecules represents an important determinant for allele specificity in US11-mediated degradation. HLA-E becomes sensitive to US11-mediated down-regulation when its cytoplasmic tail is extended. Interestingly, this only requires two additional residues, lysine and valine, at its C-terminus. For US2, the MHC class I allele specificity is largely determined by a small region at the junction of the alpha2/alpha3 domain of the HC. It is quite remarkable that minor changes, in only four residues, can completely revert the sensitivity of naturally US2-resistant HLA-E molecules. With this study we provide better insights into the features underlying the selectivity in MHC class I down-regulation by US2 and US11.
Barel
Martine T
MT
Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Pizzato
Nathalie
N
Le Bouteiller
Philippe
P
Wiertz
Emmanuel J H J
EJ
Lenfant
Francoise
F
D000483:Alleles; D000818:Animals; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D000097625:HLA-E Antigens
D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D046988:Proteasome Endopeptidase Complex; D016601:RNA-Binding Proteins; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D000097625:HLA-E Antigens; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus