TY - JOUR
T1 - Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP
AU - Luteijn, Rutger D.
AU - Hoelen, Hanneke
AU - Kruse, Elisabeth
AU - Van Leeuwen, Wouter F.
AU - Grootens, Jennine
AU - Horst, Daniëlle
AU - Koorengevel, Martijn
AU - Drijfhout, Jan W.
AU - Kremmer, Elisabeth
AU - Früh, Klaus
AU - Neefjes, Jacques J.
AU - Killian, Antoinette
AU - Lebbink, Robert Jan
AU - Ressing, Maaike E.
AU - Wiertz, Emmanuel J.H.J.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/8/15
Y1 - 2014/8/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1400964
DO - 10.4049/jimmunol.1400964
M3 - Article
C2 - 25024387
AN - SCOPUS:84905969295
SN - 0022-1767
VL - 193
SP - 1578
EP - 1589
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -