Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP

Rutger D. Luteijn, Hanneke Hoelen, Elisabeth Kruse, Wouter F. Van Leeuwen, Jennine Grootens, Daniëlle Horst, Martijn Koorengevel, Jan W. Drijfhout, Elisabeth Kremmer, Klaus Früh, Jacques J. Neefjes, Antoinette Killian, Robert Jan Lebbink, Maaike E. Ressing, Emmanuel J.H.J. Wiertz

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

CD8+ CTLs detect virus-infected cells through recognition of virus-derived peptides presented at the cell surface by MHC class I molecules. The cowpox virus protein CPXV012 deprives the endoplasmic reticulum (ER) lumen of peptides for loading onto newly synthesized MHC class I molecules by inhibiting the transporter associated with Ag processing (TAP). This evasion strategy allows the virus to avoid detection by the immune system. In this article, we show that CPXV012, a 9-kDa type II transmembrane protein, prevents peptide transport by inhibiting ATP binding to TAP. We identified a segment within the ER-luminal domain of CPXV012 that imposes the block in peptide transport by TAP. Biophysical studies show that this domain has a strong affinity for phospholipids that are also abundant in the ER membrane. We discuss these findings in an evolutionary context and show that a frameshift deletion in the CPXV012 gene in an ancestral cowpox virus created the current form of CPXV012 that is capable of inhibiting TAP. In conclusion, our findings indicate that the ER-luminal domain of CPXV012 inserts into the ER membrane, where it interacts with TAP. CPXV012 presumably induces a conformational arrest that precludes ATP binding to TAP and, thus, activity of TAP, thereby preventing the presentation of viral peptides to CTLs.

Original languageEnglish (US)
Pages (from-to)1578-1589
Number of pages12
JournalJournal of Immunology
Volume193
Issue number4
DOIs
StatePublished - Aug 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Luteijn, R. D., Hoelen, H., Kruse, E., Van Leeuwen, W. F., Grootens, J., Horst, D., Koorengevel, M., Drijfhout, J. W., Kremmer, E., Früh, K., Neefjes, J. J., Killian, A., Lebbink, R. J., Ressing, M. E., & Wiertz, E. J. H. J. (2014). Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP. Journal of Immunology, 193(4), 1578-1589. https://doi.org/10.4049/jimmunol.1400964