Kaposi's sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis.
Down-regulation of the cell surface display of class I MHC proteins is an important mechanism of immune evasion by human and animal viruses. Herpesviruses in particular encode a variety of proteins that function to lower MHC I display by several mechanisms. These include binding and retention of MHC I chains in the endoplasmic reticulum, dislocation of class I chains from the ER, inhibition of the peptide transporter (TAP) involved in antigen presentation, and shunting of newly assembled chains to lysosomes. Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a human herpesvirus strongly linked to the development of KS and to certain AIDS-associated lymphoproliferative disorders. Here we show that KSHV encodes two distinctive gene products that function to dramatically reduce cell surface MHC I expression. These viral proteins are localized predominantly to the ER. However, unlike previously described MHC I inhibitors, they do not interfere with the synthesis, translocation, or assembly of class I chains, nor do they retain them in the ER. Rather, they act to enhance endocytosis of MHC I from the cell surface; internalized class I chains are delivered to endolysosomal vesicles, where they undergo degradation. These KSHV proteins define a mechanism of class I down-regulation distinct from the mechanisms of other herpesviruses and are likely to contribute importantly to immune evasion during viral infection.
Coscoy
L
L
Howard Hughes Medical Institute and Departments of Microbiology and Medicine, University of California, San Francisco, CA 94143, USA.
Ganem
D
D
D000595:Amino Acid Sequence; D001692:Biological Transport; D004705:Endocytosis; D019084:Fluorescent Antibody Technique, Indirect; D005814:Genes, Viral; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D014764:Viral Proteins / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins