Viruses exploit the ubiquitin system by targeting cell-surface receptors recognized by immune cells for internalization, thereby evading recognition. We have characterized the KSHV (Kaposi's sarcoma-associated herpesvirus)-encoded E3 ubiquitin ligases, K3 and K5. We find their activities not only prevent recognition by cytotoxic T-lymphocytes, but also promote evasion of NK (natural killer) cells. NK cells recognize and lyse virus-infected cells expressing ligands for activatory receptors such as NKG2D (NK group 2D). K5 down-regulates cell-surface expression of the NKG2D ligands MICA/B (MHC class I-related chains A and B) by ubiquitination of MIC cytoplasmic tail lysine residues. Ubiquitination results in redistribution of MICA from the plasma membrane to an intracellular compartment, but does not result in an increased rate of degradation. Furthermore, K5 down-regulates cell-surface expression of another NK cell activatory receptor ligand, AICL (activation-induced C-type lectin). This activity requires the K5 RING (really interesting new gene)-CH domain and AICL cytoplasmic tail lysine residues. MICA and AICL down-regulation by K5 reduces NK cell-mediated cytotoxicity towards target cells, thus providing KSHV with an NK cell evasion mechanism.

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