8.B.25 The Viral Glycoprotein N (GN; UL49.5) TAP Inhibitor (GN-I) Family

TAP translocates virus-derived peptides from the cytosol into the endoplasmic reticulum, where the peptides are loaded onto MHC class I molecules. This process is crucial for the detection of virus-infected cells by CTL that recognize the MHC class I-peptide complexes at the cell surface (Verweij et al. 2008). The varicellovirus bovine herpesvirus 1 encodes a protein, UL49.5 or GN-1, that acts as a potent inhibitor of TAP (TC# 3.A.1.209.1). UL49.5 acts in two ways: 1) by blocking conformational changes of TAP required for the translocation of peptides into the endoplasmic reticulum, and 2) by targeting TAP1 and TAP2 for proteasomal degradation. TAP is the target of UL49.5 within the peptide-loading complex. The presence of TAP1 and TAP2 is required for efficient interaction with UL49.5. The 6+6 trans-membrane core complex of TAP is sufficient for UL49.5 to interact with TAP and block its function.  However, UL49.5-induced inhibition of peptide transport was most efficient in cells expressing full-length TAP1 and TAP2. Inhibition by UL49.5 appeared to be independent of the presence of other peptide-loading complex components, including tapasin (Verweij et al. 2008). The N-terminus of the HSV-1-encoded UL49.5 adopts a highly flexible, unordered structure in the extracellular part due to the presence of a large number of proline and glycine residues (Karska et al. 2023). In contrast to the BoHV-1-encoded homolog, the transmembrane region of the HSV-1-encoded UL49.5 is formed by a single long transmembrane alpha-helix, rather than two helices oriented perpendicularly, while the cytoplasmic part of the protein (C-terminus) has a short unordered structure (Karska et al. 2023).