A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter

• Published in: Nature (London) Vol. 529; no. 7587; pp. 537 - 540
• Main Authors: Oldham, Michael L., Hite, Richard K., Steffen, Alanna M., Damko, Ermelinda, Li, Zongli, Walz, Thomas, Chen, Jue
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-01-2016; Nature Publishing Group
• Subjects: 631/250/2161; 631/535/1258/1259; Amino Acid Sequence; Antigen presentation; Antigens; Antigens, Viral - immunology; Antigens, Viral - metabolism; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette Transporters - ultrastructure; Cryoelectron Microscopy; Cytotoxicity; Development and progression; Endoplasmic Reticulum - metabolism; Genetic aspects; Herpesvirus 1, Human - chemistry; Herpesvirus 1, Human - immunology; Herpesvirus 1, Human - metabolism; Herpesvirus 1, Human - ultrastructure; Humanities and Social Sciences; Immediate-Early Proteins - chemistry; Immediate-Early Proteins - metabolism; Immediate-Early Proteins - ultrastructure; Immune Evasion; Immune response; Immune system; letter; Lymphocytes; Models, Molecular; Molecular Sequence Data; multidisciplinary; Peptides; Physiological aspects; Protein Binding; Protein Conformation; Proteins; Science; Studies; T cells; Translocation; Virus diseases; Viruses; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature16506

The cryo-electron microscopy structure of human TAP transporter, a peptide transporter central to MHC class I antigen presentation and cellular immunity, in complex with the herpes simplex virus protein ICP47.
A viral immune evasion mechanism
Jue Chen and colleagues provide the first cryo-electron microscopy structure of the TAP transporter, a peptide transporter central to MHC class I antigen presentation and cellular immunity. The authors solve the structure of TAP in complex with the herpes virus protein ICP47, and reveal how the herpes virus protein plugs a long helical hairpin into the peptide translocation pathway of TAP, thereby blocking viral antigens from entering the endoplasmic reticulum and facilitating immune evasion.
Cellular immunity against viral infection and tumour cells depends on antigen presentation by major histocompatibility complex class I (MHC I) molecules. Intracellular antigenic peptides are transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) and then loaded onto the nascent MHC I molecules, which are exported to the cell surface and present peptides to the immune system
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. Cytotoxic T lymphocytes recognize non-self peptides and program the infected or malignant cells for apoptosis. Defects in TAP account for immunodeficiency and tumour development. To escape immune surveillance, some viruses have evolved strategies either to downregulate TAP expression or directly inhibit TAP activity. So far, neither the architecture of TAP nor the mechanism of viral inhibition has been elucidated at the structural level. Here we describe the cryo-electron microscopy structure of human TAP in complex with its inhibitor ICP47, a small protein produced by the herpes simplex virus I. Here we show that the 12 transmembrane helices and 2 cytosolic nucleotide-binding domains of the transporter adopt an inward-facing conformation with the two nucleotide-binding domains separated. The viral inhibitor ICP47 forms a long helical hairpin, which plugs the translocation pathway of TAP from the cytoplasmic side. Association of ICP47 precludes substrate binding and prevents nucleotide-binding domain closure necessary for ATP hydrolysis. This work illustrates a striking example of immune evasion by persistent viruses. By blocking viral antigens from entering the endoplasmic reticulum, herpes simplex virus is hidden from cytotoxic T lymphocytes, which may contribute to establishing a lifelong infection in the host.