Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity

Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1656-61. doi: 10.1073/pnas.0707883105. Epub 2008 Jan 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Cell Line
  • Cytotoxicity, Immunologic*
  • Down-Regulation
  • Genes, Viral
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / immunology*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / virology*
  • Lectins, C-Type / metabolism
  • Ligands
  • Lysine / genetics
  • Lysine / metabolism
  • 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

Substances

  • CLEC2B protein, human
  • Histocompatibility Antigens Class I
  • Immediate-Early Proteins
  • K5 protein, Human herpesvirus 8
  • KLRF1 protein, human
  • KLRK1 protein, human
  • Lectins, C-Type
  • Ligands
  • MHC class I-related chain A
  • MICB antigen
  • Membrane Glycoproteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • Ubiquitin
  • Lysine