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 Frueh, Jacques J. Neefjes, Antoinette Killian, Robert Jan Lebbink, Maaike E. Ressing, Emmanuel J H J Wiertz

Research output: Contribution to journalArticle

15 Citations (Scopus)

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

Fingerprint

Cowpox virus
Endoplasmic Reticulum
Adenosine Triphosphate
Peptides
trypsinogen activation peptide
Viruses
Proteins
Membranes
Immune System
Phospholipids
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Luteijn, R. D., Hoelen, H., Kruse, E., Van Leeuwen, W. F., Grootens, J., Horst, D., ... 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

Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP. / Luteijn, Rutger D.; Hoelen, Hanneke; Kruse, Elisabeth; Van Leeuwen, Wouter F.; Grootens, Jennine; Horst, Daniëlle; Koorengevel, Martijn; Drijfhout, Jan W.; Kremmer, Elisabeth; Frueh, Klaus; Neefjes, Jacques J.; Killian, Antoinette; Lebbink, Robert Jan; Ressing, Maaike E.; Wiertz, Emmanuel J H J.

In: Journal of Immunology, Vol. 193, No. 4, 15.08.2014, p. 1578-1589.

Research output: Contribution to journalArticle

Luteijn, RD, Hoelen, H, Kruse, E, Van Leeuwen, WF, Grootens, J, Horst, D, Koorengevel, M, Drijfhout, JW, Kremmer, E, Frueh, K, Neefjes, JJ, Killian, A, Lebbink, RJ, Ressing, ME & Wiertz, EJHJ 2014, 'Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP', Journal of Immunology, vol. 193, no. 4, pp. 1578-1589. https://doi.org/10.4049/jimmunol.1400964
Luteijn RD, Hoelen H, Kruse E, Van Leeuwen WF, Grootens J, Horst D et al. Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP. Journal of Immunology. 2014 Aug 15;193(4):1578-1589. https://doi.org/10.4049/jimmunol.1400964
Luteijn, Rutger D. ; Hoelen, Hanneke ; Kruse, Elisabeth ; Van Leeuwen, Wouter F. ; Grootens, Jennine ; Horst, Daniëlle ; Koorengevel, Martijn ; Drijfhout, Jan W. ; Kremmer, Elisabeth ; Frueh, Klaus ; Neefjes, Jacques J. ; Killian, Antoinette ; Lebbink, Robert Jan ; Ressing, Maaike E. ; Wiertz, Emmanuel J H J. / Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP. In: Journal of Immunology. 2014 ; Vol. 193, No. 4. pp. 1578-1589.
@article{c6e80ae786464b639d7f9ad54b250db9,
title = "Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP",
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.",
author = "Luteijn, {Rutger D.} and Hanneke Hoelen and Elisabeth Kruse and {Van Leeuwen}, {Wouter F.} and Jennine Grootens and Dani{\"e}lle Horst and Martijn Koorengevel and Drijfhout, {Jan W.} and Elisabeth Kremmer and Klaus Frueh and Neefjes, {Jacques J.} and Antoinette Killian and Lebbink, {Robert Jan} and Ressing, {Maaike E.} and Wiertz, {Emmanuel J H J}",
year = "2014",
month = "8",
day = "15",
doi = "10.4049/jimmunol.1400964",
language = "English (US)",
volume = "193",
pages = "1578--1589",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "4",

}

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 - Frueh, Klaus

AU - Neefjes, Jacques J.

AU - Killian, Antoinette

AU - Lebbink, Robert Jan

AU - Ressing, Maaike E.

AU - Wiertz, Emmanuel J H J

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.

UR - http://www.scopus.com/inward/record.url?scp=84905969295&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905969295&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1400964

DO - 10.4049/jimmunol.1400964

M3 - Article

C2 - 25024387

AN - SCOPUS:84905969295

VL - 193

SP - 1578

EP - 1589

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 4

ER -