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).



This family belongs to the .

 

References:

Karska, N., M. Graul, E. Sikorska, I. Zhukov, M.J. Ślusarz, F. Kasprzykowski, A.D. Lipińska, and S. Rodziewicz-Motowidło. (2019). Structure determination of UL49.5 transmembrane protein from bovine herpesvirus 1 by NMR spectroscopy and molecular dynamics. Biochim. Biophys. Acta. Biomembr 1861: 926-938.

Verweij, M.C., D. Koppers-Lalic, S. Loch, F. Klauschies, H. de la Salle, E. Quinten, P.J. Lehner, A. Mulder, M.R. Knittler, R. Tampé, J. Koch, M.E. Ressing, and E.J. Wiertz. (2008). 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. J Immunol 181: 4894-4907.

Examples:

TC#NameOrganismal TypeExample
8.B.25.1.1

Viral protein inhibitor of the TAP ABC transporter (TC# 3.A.1.209.1) of 98 aas and 2 TMSs (Verweij et al. 2008).

Glycoprotein N of Suid herpesvirus 1 (SuHV-1) (Pseudorabies virus)

 
8.B.25.1.2

GN polyprotein protein product, UL49.5, of 96 aas and 2 TMSs. It is an inhibitor of the transporter associated with antigen processing (TAP) system (TC# 3.A.1.209.1), and it's 3-D structure has been determined (Karska et al. 2019).  UL49.5 contains an extracellular region (residues 1-35) and a transmembrane-intracellular segment (residues 36-75), with a flexible membrane-proximal helical structure in the extracellular part, two short alpha-helices in the transmembrane region, and an unordered structure for the cytoplasmic part. Karska et al. 2019 propose three different orientations of UL49.5 when in complex with TAP.

GN of Bovine herpes virus

 
8.B.25.1.3

GN1 of 95 aas and 2 TM

GN1 of Feline herpesvirus 1 (FeHV-1) (Feline viral rhinotracheitis virus)

 
8.B.25.1.4

GN1 or UL49.5 of 87 aas and 2 TMSs.  May be N-terminally truncated.

GN1 of Human herpesvirus 3 (HHV-3) (Varicella-zoster virus)

 
8.B.25.1.5

UL49.5 of 95 aas and 2 TMSs

UL49.5 of Gallid herpesvirus 3

 
8.B.25.1.6

Human herpes virus GN1 of 91 aas

GN1 of Human herpesvirus 1 (HHV-1) (Human herpes simplex virus 1)

 
8.B.25.1.7

UL49.5 of 97 aas and 2 TMSs

UL49.5 of Leporid herpesvirus 4

 
8.B.25.1.8

Glycoprotein N of 78 aas and 2 TMSs

GN of Cercopithecine herpesvirus 16 (CeHV-16) (Herpesvirus papio 2)

 
Examples:

TC#NameOrganismal TypeExample
8.B.25.2.1

BLRF1 or GN of 102 aas and 2 TMSs

BLRF1 of Epstein-Barr virus (HHV-4) (Human herpesvirus 4)

 
8.B.25.2.2

Envelope glycoprotein N, UL73, of 104 aas and 2 TMSs

UL73 of Simian cytomegalovirus

 
8.B.25.2.3

gpUL73 of 134 aas and 2 TMSs

gpUL73 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5)