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Natural killer (NK) cells are important early mediators of host immunity to viral infections. The NK activatory receptors NKG2D and NKp80, both C-type lectin-like homodimeric receptors, stimulate NK cell cytotoxicity toward target cells. Like other herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) down-regulates MHC class I molecules to avoid detection by cytotoxic T lymphocytes but renders cells susceptible to NK cell cytotoxicity. We now show that the KSHV immune evasion gene, K5, reduces cell surface expression of the NKG2D ligands MHC class I-related chain A (MICA), MICB, and the newly defined ligand for NKp80, activation-induced C-type lectin (AICL). Down-regulation of both MICA and AICL requires the ubiquitin E3 ligase activity of K5 to target substrate cytoplasmic tail lysine residues. The common MICA *008 allele has a frameshift mutation leading to a premature stop codon and is resistant to down-regulation because of the loss of lysine residues. K5-mediated ubiquitylation signals internalization but not degradation of MICA and causes a potent reduction in NK cell-mediated cytotoxicity. The down-regulation of ligands for both the NKG2D and NKp80 activation pathways provides KSHV with a powerful mechanism for evasion of NK cell antiviral functions.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





1656 - 1661


Alleles, Amino Acid Sequence, Cell Line, Cytotoxicity, Immunologic, Down-Regulation, Genes, Viral, Herpesvirus 8, Human, Histocompatibility Antigens Class I, Humans, Immediate-Early Proteins, Killer Cells, Natural, Lectins, C-Type, Ligands, Lysine, Lysosomes, Membrane Glycoproteins, Molecular Sequence Data, NK Cell Lectin-Like Receptor Subfamily K, Receptors, Immunologic, Receptors, Natural Killer Cell, Ubiquitin