The human cytomegalovirus (HCMV) protein US6 inhibits the transporter associated with antigen processing (TAP). Since TAP transports antigenic peptides into the endoplasmic reticulum for binding to major histocompatibility class I molecules, inhibition of the transporter by HCMV US6 impairs the presentation of viral antigens to cytotoxic T lymphocytes. HCMV US6 inhibits ATP binding by TAP, hence depriving TAP of the energy source it requires for peptide translocation, yet the molecular basis for the interaction between US6 and TAP is poorly understood. In this study we demonstrate that residues 89 to 108 of the HCMV US6 luminal domain are required for TAP inhibition, whereas sequences that flank this region stabilize the binding of the viral protein to TAP. In parallel, we demonstrate that chimpanzee cytomegalovirus (CCMV) US6 binds, but does not inhibit, human TAP. The sequence of CCMV US6 differs from that of HCMV US6 in the region corresponding to residues 89 to 108 of the HCMV protein. The substitution of this region of CCMV US6 with the corresponding residues from HCMV US6 generates a chimeric protein that inhibits human TAP and provides further evidence for the pivotal role of residues 89 to 108 of HCMV US6 in the inhibition of TAP. On the basis of these observations, we propose that there is a hierarchy of interactions between HCMV US6 and TAP, in which residues 89 to 108 of HCMV US6 interact with and inhibit TAP, whereas other parts of the viral protein also bind to TAP and stabilize this inhibitory interaction.The major histocompatibility (MHC) class I antigen presentation pathway plays a central role in the immune response to viral infection. MHC class I molecules are expressed on the plasma membranes of all nucleated cells and present peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs). CTLs monitor these MHC class I molecules for peptides derived from viral proteins and kill the infected cells. The presentation of antigenic peptides to CTLs represents the end point of a complex multistep pathway. The vast majority of peptides presented by MHC class I molecules are generated by the degradation of proteins in the cytosol by the proteasome complex (38). These peptides are then translocated into the lumen of the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) (1). MHC class I molecules are assembled in the ER by a process that involves ER-resident chaperones (5). Peptide binding represents the final step of MHC class I molecule folding and is facilitated by the TAP-associated molecule tapasin, which links the nascent MHC class I molecules to TAP to form the "peptide-loading complex" (5). Only once they have bound peptides can MHC class I molecules dissociate from this complex and exit the ER for transport to the plasma membrane.TAP is a member of the ATP binding cassette (ABC) family of transporters, whose members couple ATP hydrolysis to the translocation of a broad spectrum of different substrates across cellular membranes (1,29,42). All...
The major histocompatibility (MHC) class I antigen presentation pathway plays a pivotal role in immunity to viruses. MHC class I molecules are expressed on the cell surface of all nucleated cells and present peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs), which then eliminate virally infected cells. However, many viruses have evolved proteins to inhibit the MHC class I pathway, thus enabling virally infected cells to escape CTL lysis. In this review, we summarize recent findings about viral inhibition of the MHC class I pathway.
Human cytomegalovirus protein US6 inhibits the transporter associated with antigen processing (TAP), which transports peptides into the endoplasmic reticulum (ER) for binding to major histocompatibility complex (MHC) class I molecules. We demonstrate that, in TAP-deficient cells, US6 is retained in the ER and binds to calnexin, but does not inhibit cell-surface expression of HLA-A201, an MHC class I allele that binds to peptides whose import into the ER is TAPindependent. Furthermore, in TAP-positive cells, US6 reduces the cell-surface expression of HLA-B2705, an MHC class I allele that is dependent on TAP for peptide binding, to a greater extent than that of HLA-A201. These data demonstrate that US6 has differential effects on the cell-surface expression of MHC class I alleles and are consistent with TAP being the sole inhibitory target of US6 in the MHC class I antigen-presentation pathway.Major histocompatibility complex (MHC) class I molecules present peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs). CTLs monitor MHC class I molecules for peptides derived from viral antigens and kill virus-infected cells. Most peptides presented by MHC class I molecules are generated by the cytosolic proteasome complex (Rock & Goldberg, 1999). These peptides are translocated by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum (ER) lumen (Abele & Tampe, 2004), which is the site of the chaperone-dependent folding of MHC class I molecules (Antoniou et al., 2003;Peaper & Cresswell, 2008). Peptide binding represents the final step of MHC class I assembly and is facilitated by tapasin, which links the nascent MHC class I molecules and the associated chaperones calreticulin and ERp57 to TAP to form the peptide-loading complex (Antoniou et al., 2003;Peaper & Cresswell, 2008). Once peptide-bound, MHC class I molecules dissociate from this complex and traffic to the plasma membrane.Human cytomegalovirus (HCMV) encodes a cohort of proteins that inhibit the MHC class I antigen-presentation pathway (Hewitt, 2003;Hewitt & Dugan, 2004). These include US6, an ER-localized type I integral membrane glycoprotein that inhibits peptide translocation by TAP (Ahn et al., 1997; Hengel et al., 1997;Lehner et al., 1997). This blocks the supply of peptides for binding to MHC class I molecules and hence impairs recognition by CTLs (Ahn et al., 1997; Hengel et al., 1997;Lehner et al., 1997). The inhibition of ATP binding is an indirect conformational effect, as the ER-luminal domain of HCMV US6 is sufficient to inhibit ATP binding by the cytosolic nucleotide-binding domain of the TAP1 subunit (Hewitt et al., 2001; Kyritsis et al., 2001). Recently, we demonstrated that residues 89-108 of the US6 luminal domain are required for inhibition of TAP, whereas other parts of US6 bind to TAP and stabilize this inhibitory interaction (Dugan & Hewitt, 2008). Yet, whilst US6 binds to TAP, it is not known whether this interaction retains US6 in the ER or whether US6 can inhibit MHC class I expressi...
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