A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter
Oldham, Michael L.
Hite, Richard K.
Steffen, Alanna M.
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CitationOldham, Michael L., Richard K. Hite, Alanna M. Steffen, Ermelinda Damko, Zongli Li, Thomas Walz, and Jue Chen. 2015. “A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter.” Nature 529 (7587): 537-540. doi:10.1038/nature16506. http://dx.doi.org/10.1038/nature16506.
AbstractCellular immunity against viral infection and tumor cells depends on antigen presentation by the major histocompatibility complex class 1 molecules (MHC I). Intracellular antigenic peptides are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) and then loaded onto the nascent MHC I, which are exported to the cell surface and present peptides to the immune system1. Cytotoxic T lymphocytes recognize non-self peptides and program the infected or malignant cells for apoptosis. Defects in TAP account for immunodeficiency and tumor development. To escape immune surveillance, some viruses have evolved strategies to either down-regulate TAP expression or directly inhibit TAP activity. To date neither the architecture of TAP nor the mechanism of viral inhibition has been elucidated at the structural level. In this study we describe the cryo-electron microscopy (cryo-EM) structure of human TAP in complex with its inhibitor ICP47, a small protein produced by the herpes simplex virus I. We show that the twelve transmembrane helices and two cytosolic nucleotide-binding domains (NBDs) of the transporter adopt an inward-facing conformation with the two NBDs 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 also prevents NBD closure necessary for ATP hydrolysis. This work illustrates a striking example of immune evasion by persistent viruses. By blocking viral antigens from entering the ER, herpes simplex virus is hidden from cytotoxic T lymphocytes, which may contribute to establishing a lifelong infection in the host.
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