| Popis: |
NK cells are of crucial importance in the early control of murine cytomegalovirus (MCMV) infection. One of the most potent activating NK cell receptor is NKG2D that recognizes different MHC class I-like molecules. Up to now, three NKG2D ligands have been identified in mice: RAE-1, H60 and MULT-1. We have previously shown that MCMV down-regulates NKG2D ligands from the surface of infected cells and identified MCMV m152/gp40 as a regulator of NKG2D ligands (Krmpotic A. et al, Nat Immunol, 3:529, 2002). Subsequent studies identified RAE-1 as the target for m152/gp40-mediated down-regulation (Lodoen M. et al, J Exp Med, 197: 1245, 2003). Recently, we identified two additional proteins encoded by viral m145 (Krmpotic A. et al, J Exp Med, 201: 211, 2005) and m155 (Hasan M. et al, J Virol, 79: 2920, 2005) genes, which are responsible for the down-regulation of NKG2D ligands MULT-1 and H60, respectively. Our results indicated the involvement of an additional, so far unknown, MCMV gene in the regulation of H60. The importance of m145 and m155 genes in the evasion of NK cells was confirmed also in vivo, underlying the significance of the escape of NKG2D signaling for viral survival and maintenance. Acquisition of EndoH resistance and preserved half-life of H60 and MULT-1 in MCMV infected cells indicate that viral inhibitors affect expression of these proteins only after their exit from the ERGIC/cis-Golgi compartment. In an attempt to identify potential mechanisms by which m145 and m155 interfere with their cellular targets, the co-localization of H60 and MULT-1 proteins with different cellular compartments have been investigated. MULT-1 and H60 co-localize with TGN in uninfected and infected cells confirming that in infected cells both proteins can reach this compartment. The co-localization of MULT-1 and H60 with endo-lysosomal compartment is increased in infected cells. Furthermore different inhibitors of endocytosis and protein degradation were used. We showed that the downmodulation of surface MULT-1 in MCMV infected cells is mediated via clathrin dependent endocytosis and that both ligands, H60 and MULT-1, are subject of protein degradation in lysosomes. |
