Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity.
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.
Thomas
Mair
M
Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Hills Road, Cambridge CB2 0XY, United Kingdom.
Boname
Jessica M
JM
Field
Sarah
S
Nejentsev
Sergey
S
Salio
Mariolina
M
Cerundolo
Vincenzo
V
Wills
Mark
M
Lehner
Paul J
PJ
D000483:Alleles; D000595:Amino Acid Sequence; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D005814:Genes, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000821:virology*; D037181:Lectins, C-Type / Q000378:metabolism; D008024:Ligands; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D055607:Receptors, Natural Killer Cell; D025801:Ubiquitin / Q000378:metabolism
C104778:CLEC2B protein, human; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; C405867:K5 protein, Human herpesvirus 8; C431711:KLRF1 protein, human; C527085:KLRK1 protein, human; D037181:Lectins, C-Type; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D025801:Ubiquitin; D008239:Lysine