Varicellovirus UL49.5 Proteins Differentially Affect the Function of the Transporter Associated with Antigen Processing, TAP

Abstract

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.

Antigen processing and presentation: TAPping into ABC transporters

“…Other viral inhibitors arrest TAP in a translocation-incompetent state. US6 of human cytomegalovirus (HCMV) and UL49.5 of equine herpesvirus (EHV) types 1 and 4 lock TAP in a state that can still bind antigenic peptides, but block the interaction of TAP with ATP [51][52][53][54][55][56].…”

“…The UL49.5 proteins of BHV-1 and pseudorabies virus (PRV) arrest TAP in a state that can still bind peptides without preventing ATP interactions [49,51]. Finally, the cytosolic ICP47 proteins of herpes simplex viruses (HSV) block the TAP peptide-binding cavity by competing with antigenic peptides [57,58].…”

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

“…Although all herpesviruses encode a homologue of the UL49.5 protein (also called glycoprotein N), inhibition of TAP by UL49.5 appears to be restricted to a subset of the genus Varicelloviruses, including bovine herpesvirus 1 (BHV-1), pseudorabies virus, equine herpesvirus 1 and 4, and canine herpesvirus (38,39). ICP47, US6, BNLF2a, and UL49.5 are structurally unrelated, and the molecular mechanisms through which they block TAP are different.…”

Polarisation of equine pregnancy outcome associated with a maternal MHC class I allele: Preliminary evidence

“…No statistically significant associations were found between pregnancy loss and mares' age, (Huang et al, 2015) and block the formation of peptide-MHC class I complexes in the transport associated pathway involved in antigen presentation (Koppers-Lalic et al, 2008). Bodo et al, (1994) has reported an association between the ELA-A10 haplotype and higher EHV-1 specific, virus neutralising antibody titres in peripheral blood, compared with other haplotypes.…”