Abstract
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 language | English |
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Pages (from-to) | 1656-61 |
Number of pages | 6 |
Journal | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA |
Volume | 105 |
Issue number | 5 |
DOIs | |
Publication status | Published - 5 Feb 2008 |
Externally published | Yes |
Keywords
- Alleles
- Amino Acid Sequence
- Cell Line
- Cytotoxicity, Immunologic
- Down-Regulation
- Genes, Viral
- Herpesvirus 8, Human/genetics
- Histocompatibility Antigens Class I/genetics
- Humans
- Immediate-Early Proteins/genetics
- Killer Cells, Natural/immunology
- Lectins, C-Type/metabolism
- Ligands
- Lysine/genetics
- Lysosomes/metabolism
- Membrane Glycoproteins/metabolism
- Molecular Sequence Data
- NK Cell Lectin-Like Receptor Subfamily K
- Receptors, Immunologic/antagonists & inhibitors
- Receptors, Natural Killer Cell
- Ubiquitin/metabolism