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101. Additional file 1: of Comprehensive profiling of functional Epstein-Barr virus miRNA expression in human cell lines

Author

Hooykaas, Marjolein, Kruse, Elisabeth, Wiertz, Emmanuel, and Lebbink, Robert

Abstract

List of miRNA sequences and perfect target sequences. List of miRNA sequences annotated in miRBase or (*) based on deep sequencing data from Chen et al. 2010 (column 2). Perfect target sequences (column 3) were cloned downstream of the mCherry reporter gene to monitor miRNA expression. # The deep-sequencing analysis in Fig. 3 identified a single nucleotide change (position 17, T changed to C) in the mature miR-BART19-5p miRNA sequence in the C666-1 strain. Therefore, the miR-BART19-5p miRNA sensor used in the C666-1 cells to monitor miRNA activity does not fully match the miR-BART19-5p sequence expressed in these cells (DOCX 20 kb)

Published
2016
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102. Additional file 6: of Comprehensive profiling of functional Epstein-Barr virus miRNA expression in human cell lines

Author

Hooykaas, Marjolein, Kruse, Elisabeth, Wiertz, Emmanuel, and Lebbink, Robert

Subjects
hemic and lymphatic diseases
Abstract

AKBM cells are EBV positive. A) Schematic representation of the EBV super-sensor. Five perfect EBV miRNA target sites were cloned downstream of the mCherry reporter gene. The vector allows for sensing of EBV presence by monitoring the combined functional expression of 5 EBV miRNAs. B) EBV-positive AKBM cells and EBV negative AK31 and 2A8 cells were either left untreated (cells alone), were transduced with an mCherry-control vector (control sensor), or were transduced with the EBV sensor from a). Cells were monitored for mCherry reporter expression at 7Â days post transduction by flow cytometry (PDF 165 kb)

Published
2016
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103. Additional file 4: of Comprehensive profiling of functional Epstein-Barr virus miRNA expression in human cell lines

Author

Hooykaas, Marjolein, Kruse, Elisabeth, Wiertz, Emmanuel, and Lebbink, Robert

Subjects
hemic and lymphatic diseases
Abstract

Assessment of miRNA reporters in EBV− cells. Reporter activity for miR-BART2-3p, miR-BART3-5p and controls was compared between AKBM and the EBV− Burkitt’s lymphoma cell lines, 2A8 and AK31 (AKBM data also shown in Fig. 1). The miR-BART2-3p reporter is only downregulated in AKBM but not in the other two cell lines, suggesting that downregulation of the reporter is specific for EBV+ cells and thus likely due to miR-BART2-3p expression. The miR-BART3-5p reporter was downregulated in all three cell lines, suggesting the influence of a common host cell factor such as a human miRNA on reporter expression (PDF 101 kb)

Published
2016
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104. Additional file 3: of Comprehensive profiling of functional Epstein-Barr virus miRNA expression in human cell lines

Author

Hooykaas, Marjolein, Kruse, Elisabeth, Wiertz, Emmanuel, and Lebbink, Robert

Abstract

Comparison of functional EBV miRNA expression between AKBM and other EBV+ cell lines. miRNA reporter expression (data also shown in Fig. 1) was compared between AKBM and the three other EBV+ cell lines. Every dot represents the relative reporter expression of a specific miRNA as a percentage of the control reporter. The dashed line indicates the diagonal (no difference in relative reporter expression between both cell lines) (PDF 91 kb)

Published
2016
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105. EBV MicroRNA BART16 Suppresses Type I IFN Signaling

Author

Hooykaas, Marjolein J. G., primary, van Gent, Michiel, additional, Soppe, Jasper A., additional, Kruse, Elisabeth, additional, Boer, Ingrid G. J., additional, van Leenen, Dik, additional, Groot Koerkamp, Marian J. A., additional, Holstege, Frank C. P., additional, Ressing, Maaike E., additional, Wiertz, Emmanuel J. H. J., additional, and Lebbink, Robert Jan, additional

Published
2017
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107. Pathogenicity of Bovine Neonatal Pancytopenia-associated vaccine-induced alloantibodies correlates with Major Histocompatibility Complex class I expression

Author

Benedictus, Lindert, Luteijn, Rutger D, Otten, Henny, Jan Lebbink, Robert, van Kooten, Peter J S, Wiertz, Emmanuel J H J, Rutten, Victor P M G, Koets, Ad P, Infection & Immunity, dIRAS RA-I&I RA, Risk Assessment, LS Immunologie, Sub Immunologie, Infection & Immunity, dIRAS RA-I&I RA, Risk Assessment, LS Immunologie, and Sub Immunologie

Subjects
Pancytopenia, Cattle Diseases, Research Support, Major histocompatibility complex, Article, Cell Line, Antigen, Antibody Specificity, Isoantibodies, Pregnancy, MHC class I, Journal Article, medicine, Animals, Humans, cardiovascular diseases, Non-U.S. Gov't, Multidisciplinary, Bovine Neonatal Pancytopenia, biology, Adverse effects, Integrin beta1, Research Support, Non-U.S. Gov't, Histocompatibility Antigens Class I, Viral Vaccines, medicine.disease, alloantibodies, Virology, Histocompatibility, medicine.anatomical_structure, Immunology, biology.protein, cardiovascular system, very late antigen-3, Cattle, Female, Bone marrow, Antibody, Lymphocytopenia, human activities, hormones, hormone substitutes, and hormone antagonists
Abstract

Bovine Neonatal Pancytopenia (BNP), a fatal bleeding syndrome of neonatal calves, is caused by maternal alloantibodies absorbed from colostrum and is characterized by lymphocytopenia, thrombocytopenia and bone marrow hypoplasia. An inactivated viral vaccine is the likely source of alloantigens inducing BNP-associated alloantibodies in the dam. In this study the specificity of BNP alloantibodies was assessed and was linked to the pathology of BNP. We demonstrated that Major Histocompatibility Complex class I (MHC I) and Very Late Antigen-3, an integrin α3/β1 heterodimer, were the major targets of BNP alloantibodies. However, alloantibody binding to various bovine cell types correlated with MHC I expression, rather than integrin β1 or α3 expression. Likewise, alloantibody-dependent complement-mediated cell lysis correlated strongly with MHC I expression. Examination of several tissues of third trimester bovine foetuses revealed that cells, shown to be affected in calves with BNP, were characterized by high MHC class I expression and high levels of alloantibody binding. We conclude that in spite of the heterogeneous specificity of BNP associated maternal alloantibodies, MHC I-specific antibodies mediate the pathogenicity of BNP in the calf and that cells with high MHC I expression were preferentially affected in BNP.

Published
2015

109. EBV MicroRNA BART16 suppresses Type i IFN signaling

Author

Hooykaas, Marjolein J.G., Van Gent, Michiel, Soppe, Jasper A., Kruse, Elisabeth, Boer, Ingrid G.J., Van Leenen, Dik, Groot Koerkamp, Marian J.A., Holstege, Frank C.P., Ressing, Maaike E., Wiertz, Emmanuel J.H.J., Lebbink, Robert Jan, Hooykaas, Marjolein J.G., Van Gent, Michiel, Soppe, Jasper A., Kruse, Elisabeth, Boer, Ingrid G.J., Van Leenen, Dik, Groot Koerkamp, Marian J.A., Holstege, Frank C.P., Ressing, Maaike E., Wiertz, Emmanuel J.H.J., and Lebbink, Robert Jan

Published
2017

113. Multiple E2 ubiquitin-conjugating enzymes regulate human cytomegalovirus US2-mediated immunoreceptor downregulation

Author

MMB Research line 3a, Infection & Immunity, van de Weijer, Michael L., Schuren, Anouk B.C., Boomen, Dick J.H., Mulder, Arend, Claas, Frans H J, Lehner, Paul J., Lebbink, Robert Jan, Wiertz, Emmanuel J.H.J., MMB Research line 3a, Infection & Immunity, van de Weijer, Michael L., Schuren, Anouk B.C., Boomen, Dick J.H., Mulder, Arend, Claas, Frans H J, Lehner, Paul J., Lebbink, Robert Jan, and Wiertz, Emmanuel J.H.J.

Published
2017

114. EBV MicroRNA BART16 suppresses Type i IFN signaling

Author

MMB Research line 3a, Infection & Immunity, MMB Onderzoek en Onderwijs, Groep Holstege, Cancer, CMM Groep Burgering, Hooykaas, Marjolein J.G., Van Gent, Michiel, Soppe, Jasper A., Kruse, Elisabeth, Boer, Ingrid G.J., Van Leenen, Dik, Groot Koerkamp, Marian J.A., Holstege, Frank C.P., Ressing, Maaike E., Wiertz, Emmanuel J.H.J., Lebbink, Robert Jan, MMB Research line 3a, Infection & Immunity, MMB Onderzoek en Onderwijs, Groep Holstege, Cancer, CMM Groep Burgering, Hooykaas, Marjolein J.G., Van Gent, Michiel, Soppe, Jasper A., Kruse, Elisabeth, Boer, Ingrid G.J., Van Leenen, Dik, Groot Koerkamp, Marian J.A., Holstege, Frank C.P., Ressing, Maaike E., Wiertz, Emmanuel J.H.J., and Lebbink, Robert Jan

Published
2017

115. A combinational CRISPR/Cas9 gene-editing approach can halt HIV replication and prevent viral escape

Author

MMB Research line 3a, Infection & Immunity, MMB, Lebbink, Robert Jan, de Jong, Dorien C M, Wolters, Femke, Kruse, Elisabeth M, van Ham, Petra M, Wiertz, Emmanuel J H J, Nijhuis, Monique, MMB Research line 3a, Infection & Immunity, MMB, Lebbink, Robert Jan, de Jong, Dorien C M, Wolters, Femke, Kruse, Elisabeth M, van Ham, Petra M, Wiertz, Emmanuel J H J, and Nijhuis, Monique

Published
2017

118. The Epstein-Barr Virus Glycoprotein gp150 Forms an Immune-Evasive Glycan Shield at the Surface of Infected Cells

Author

Gram, Anna M, Oosenbrug, Timo, Lindenbergh, Marthe F S, Büll, Christian, Comvalius, Anouskha, Dickson, Kathryn J I, Wiegant, Joop, Vrolijk, Hans, Lebbink, Robert Jan, Wolterbeek, Ron, Adema, Gosse J, Griffioen, Marieke, Heemskerk, Mirjam H M, Tscharke, David C, Hutt-Fletcher, Lindsey M, Wiertz, Emmanuel J H J, Hoeben, Rob C, Ressing, M.E., Gram, Anna M, Oosenbrug, Timo, Lindenbergh, Marthe F S, Büll, Christian, Comvalius, Anouskha, Dickson, Kathryn J I, Wiegant, Joop, Vrolijk, Hans, Lebbink, Robert Jan, Wolterbeek, Ron, Adema, Gosse J, Griffioen, Marieke, Heemskerk, Mirjam H M, Tscharke, David C, Hutt-Fletcher, Lindsey M, Wiertz, Emmanuel J H J, Hoeben, Rob C, and Ressing, M.E.

Published
2016

120. CRISPR/Cas9-Mediated Genome Editing of Herpesviruses Limits Productive and Latent Infections

Author

van Diemen, Ferdy R., Kruse, Elisabeth M., Hooykaas, Marjolein J G, Bruggeling, Carlijn E., Schürch, Anita C., van Ham, Petra M., Imhof, Saskia M., Nijhuis, Monique, Wiertz, Emmanuel J H J, Lebbink, Robert Jan, van Diemen, Ferdy R., Kruse, Elisabeth M., Hooykaas, Marjolein J G, Bruggeling, Carlijn E., Schürch, Anita C., van Ham, Petra M., Imhof, Saskia M., Nijhuis, Monique, Wiertz, Emmanuel J H J, and Lebbink, Robert Jan

Published
2016

122. The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein

Author

MMB Research line 3a, Infection & Immunity, van de Weijer, Michael L, van Muijlwijk, Guus H, Visser, Linda J, Costa, Ana I, Wiertz, Emmanuel J H J, Lebbink, Robert Jan, MMB Research line 3a, Infection & Immunity, van de Weijer, Michael L, van Muijlwijk, Guus H, Visser, Linda J, Costa, Ana I, Wiertz, Emmanuel J H J, and Lebbink, Robert Jan

Published
2016

123. The Epstein-Barr Virus Glycoprotein gp150 Forms an Immune-Evasive Glycan Shield at the Surface of Infected Cells

Author

MMB Research line 3a, Infection & Immunity, CTI Boes, Gram, Anna M, Oosenbrug, Timo, Lindenbergh, Marthe F S, Büll, Christian, Comvalius, Anouskha, Dickson, Kathryn J I, Wiegant, Joop, Vrolijk, Hans, Lebbink, Robert Jan, Wolterbeek, Ron, Adema, Gosse J, Griffioen, Marieke, Heemskerk, Mirjam H M, Tscharke, David C, Hutt-Fletcher, Lindsey M, Wiertz, Emmanuel J H J, Hoeben, Rob C, Ressing, M.E., MMB Research line 3a, Infection & Immunity, CTI Boes, Gram, Anna M, Oosenbrug, Timo, Lindenbergh, Marthe F S, Büll, Christian, Comvalius, Anouskha, Dickson, Kathryn J I, Wiegant, Joop, Vrolijk, Hans, Lebbink, Robert Jan, Wolterbeek, Ron, Adema, Gosse J, Griffioen, Marieke, Heemskerk, Mirjam H M, Tscharke, David C, Hutt-Fletcher, Lindsey M, Wiertz, Emmanuel J H J, Hoeben, Rob C, and Ressing, M.E.

Published
2016

124. CRISPR/Cas9-Mediated Genome Editing of Herpesviruses Limits Productive and Latent Infections

Author

MMB Research line 3a, Infection & Immunity, MMB, MS Oogheelkunde, van Diemen, Ferdy R., Kruse, Elisabeth M., Hooykaas, Marjolein J G, Bruggeling, Carlijn E., Schürch, Anita C., van Ham, Petra M., Imhof, Saskia M., Nijhuis, Monique, Wiertz, Emmanuel J H J, Lebbink, Robert Jan, MMB Research line 3a, Infection & Immunity, MMB, MS Oogheelkunde, van Diemen, Ferdy R., Kruse, Elisabeth M., Hooykaas, Marjolein J G, Bruggeling, Carlijn E., Schürch, Anita C., van Ham, Petra M., Imhof, Saskia M., Nijhuis, Monique, Wiertz, Emmanuel J H J, and Lebbink, Robert Jan

Published
2016

128. The Epstein-Barr Virus Glycoprotein gp150 Forms an Immune-Evasive Glycan Shield at the Surface of Infected Cells

Author

Gram, Anna M., primary, Oosenbrug, Timo, additional, Lindenbergh, Marthe F. S., additional, Büll, Christian, additional, Comvalius, Anouskha, additional, Dickson, Kathryn J. I., additional, Wiegant, Joop, additional, Vrolijk, Hans, additional, Lebbink, Robert Jan, additional, Wolterbeek, Ron, additional, Adema, Gosse J., additional, Griffioen, Marieke, additional, Heemskerk, Mirjam H. M., additional, Tscharke, David C., additional, Hutt-Fletcher, Lindsey M., additional, Wiertz, Emmanuel J. H. J., additional, Hoeben, Rob C., additional, and Ressing, Maaike E., additional

Published
2016
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132. Pathogenicity of Bovine Neonatal Pancytopenia-associated vaccine-induced alloantibodies correlates with Major Histocompatibility Complex class I expression

Author

Infection & Immunity, dIRAS RA-I&I RA, Risk Assessment, LS Immunologie, Sub Immunologie, Benedictus, Lindert, Luteijn, Rutger D, Otten, Henny, Jan Lebbink, Robert, van Kooten, Peter J S, Wiertz, Emmanuel J H J, Rutten, Victor P M G, Koets, Ad P, Infection & Immunity, dIRAS RA-I&I RA, Risk Assessment, LS Immunologie, Sub Immunologie, Benedictus, Lindert, Luteijn, Rutger D, Otten, Henny, Jan Lebbink, Robert, van Kooten, Peter J S, Wiertz, Emmanuel J H J, Rutten, Victor P M G, and Koets, Ad P

Published
2015

133. Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97

Author

Hoelen, Hanneke, Zaldumbide, Arnaud, van Leeuwen, Wouter F, Torfs, Ellen C W, Engelse, Marten A, Hassan, Chopie, Lebbink, Robert Jan, de Koning, Eelco J, Resssing, Maaike E, de Ru, Arnoud H, van Veelen, Peter A, Hoeben, Rob C, Roep, Bart O, Wiertz, Emmanuel J H J, Hoelen, Hanneke, Zaldumbide, Arnaud, van Leeuwen, Wouter F, Torfs, Ellen C W, Engelse, Marten A, Hassan, Chopie, Lebbink, Robert Jan, de Koning, Eelco J, Resssing, Maaike E, de Ru, Arnoud H, van Veelen, Peter A, Hoeben, Rob C, Roep, Bart O, and Wiertz, Emmanuel J H J

Abstract

Patients with type 1 diabetes (T1D) suffer from beta-cell destruction by CD8+ T-cells that have preproinsulin as an important target autoantigen. It is of great importance to understand the molecular mechanism underlying the processing of preproinsulin into these CD8+ T-cell epitopes. We therefore studied a pathway that may contribute to the production of these antigenic peptides: degradation of proinsulin via ER associated protein degradation (ERAD). Analysis of the MHC class I peptide ligandome confirmed the presentation of the most relevant MHC class I-restricted diabetogenic epitopes in our cells: the signal peptide-derived sequence A15-A25 and the insulin B-chain epitopes H29-A38 and H34-V42. We demonstrate that specific silencing of Derlin-2, p97 and HRD1 by shRNAs increases steady state levels of proinsulin. This indicates that these ERAD constituents are critically involved in proinsulin degradation and may therefore also play a role in subsequent antigen generation. These ERAD proteins therefore represent interesting targets for novel therapies aiming at the reduction and possibly also prevention of beta-cell directed auto-immune reactions in T1D.

Published
2015

134. Silencing the shutoff protein of Epstein-Barr virus in productively infected B cells points to (innate) targets for immune evasion

Author

MMB Onderzoek en Onderwijs, MMB, CTI Meyaard, MMB Research line 3a, Infection & Immunity, van Gent, Michiel, Gram, Anna M, Boer, Ingrid G J, Geerdink, Ruben J, Lindenbergh, Marthe F S, Lebbink, Robert Jan, Wiertz, Emmanuel J H J, Ressing, Maaike E, MMB Onderzoek en Onderwijs, MMB, CTI Meyaard, MMB Research line 3a, Infection & Immunity, van Gent, Michiel, Gram, Anna M, Boer, Ingrid G J, Geerdink, Ruben J, Lindenbergh, Marthe F S, Lebbink, Robert Jan, Wiertz, Emmanuel J H J, and Ressing, Maaike E

Published
2015

136. Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97

Author

Hoelen, Hanneke, primary, Zaldumbide, Arnaud, additional, van Leeuwen, Wouter F., additional, Torfs, Ellen C. W., additional, Engelse, Marten A., additional, Hassan, Chopie, additional, Lebbink, Robert Jan, additional, de Koning, Eelco J., additional, Resssing, Maaike E., additional, de Ru, Arnoud H., additional, van Veelen, Peter A., additional, Hoeben, Rob C., additional, Roep, Bart O., additional, and Wiertz, Emmanuel J. H. J., additional

Published
2015
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139. CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases

Author

Sadeghi, Sheila, Wiertz, Emmanuel, Pabarcus, Michael K., Correia, Maria Almira, Hoe, Nicholas, and Patterson, Cam

Abstract

Human liver CYP3A4 is an endoplasmic reticulum (ER)-anchored hemoprotein responsible for the metabolism of >50% of clinically prescribed drugs. After heterologous expression in Saccharomyces cerevisiae,it is degraded via the ubiquitin (Ub)-dependent 26S proteasomal pathway that utilizes Ubc7p/Cue1p, but none of the canonical Ub-ligases (E3s) Hrd1p/Hrd3p, Doa10p, and Rsp5p involved in ER-associated degradation (ERAD). To identify an Ub-ligase capable of ubiquitinating CYP3A4, we examined various in vitro reconstituted mammalian E3 systems, using purified and functionally characterized recombinant components. Of these, the cytosolic domain of the ER-protein gp78, also known as the tumor autocrine motility factor receptor (AMFR), an UBC7-dependent polytopic RING-finger E3, effectively ubiquitinated CYP3A4 in vitro, as did the UbcH5a-dependent cytosolic E3 CHIP. CYP3A4 immunoprecipitation coupled with anti-Ub immunoblotting analyses confirmed its ubiquitination in these reconstituted systems. Thus, both UBC7/gp78 and UbcH5a/CHIP may be involved in CYP3A4 ERAD, although their relative physiological contribution remains to be established.

Published
2009
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142. Cowpox virus protein CPXV012 eludes CTLs by blocking ATP binding to TAP

Author

Membrane Biochemistry and Biophysics, LS Virologie, Sub Membrane Biochemistry & Biophysics, Luteijn, Rutger D., Hoelen, Hanneke, Kruse, Elisabeth, van Leeuwen, Wouter F., Grootens, Jennine, Horst, Daniëlle, Koorengevel, Martijn, Drijfhout, Jan W., Kremmer, Elisabeth, Früh, Klaus, Neefjes, Jacques J., Killian, Antoinette, Lebbink, Robert Jan, Ressing, Maaike E., Wiertz, Emmanuel J H J, Membrane Biochemistry and Biophysics, LS Virologie, Sub Membrane Biochemistry & Biophysics, Luteijn, Rutger D., Hoelen, Hanneke, Kruse, Elisabeth, van Leeuwen, Wouter F., Grootens, Jennine, Horst, Daniëlle, Koorengevel, Martijn, Drijfhout, Jan W., Kremmer, Elisabeth, Früh, Klaus, Neefjes, Jacques J., Killian, Antoinette, Lebbink, Robert Jan, Ressing, Maaike E., and Wiertz, Emmanuel J H J

Published
2014

143. Cowpox Virus Protein CPXV012 Eludes CTLs by Blocking ATP Binding to TAP

Author

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

Published
2014
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144. A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation

Author

van de Weijer, Michael L., primary, Bassik, Michael C., additional, Luteijn, Rutger D., additional, Voorburg, Cornelia M., additional, Lohuis, Mirjam A.M., additional, Kremmer, Elisabeth, additional, Hoeben, Rob C., additional, LeProust, Emily M., additional, Chen, Siyuan, additional, Hoelen, Hanneke, additional, Ressing, Maaike E., additional, Patena, Weronika, additional, Weissman, Jonathan S., additional, McManus, Michael T., additional, Wiertz, Emmanuel J.H.J., additional, and Lebbink, Robert Jan, additional

Published
2014
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145. Epstein-Barr Virus Large Tegument Protein BPLF1 Contributes to Innate Immune Evasion through Interference with Toll-Like Receptor Signaling

Author

van Gent, Michiel, primary, Braem, Steven G. E., additional, de Jong, Annemieke, additional, Delagic, Nezira, additional, Peeters, Janneke G. C., additional, Boer, Ingrid G. J., additional, Moynagh, Paul N., additional, Kremmer, Elisabeth, additional, Wiertz, Emmanuel J., additional, Ovaa, Huib, additional, Griffin, Bryan D., additional, and Ressing, Maaike E., additional

Published
2014
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147. Epstein-Barr virus isolates retain their capacity to evade T cell immunity through BNLF2a despite extensive sequence variation

Author

Horst, Daniëlle, Burrows, Scott R., Gatherer, Derek, van Wilgenburg, Bonnie, Boer, Ingrid G. J., Bell, Melissa J., Ressing, Maaike E., Wiertz, Emmanuel J. H. J., Horst, Daniëlle, Burrows, Scott R., Gatherer, Derek, van Wilgenburg, Bonnie, Boer, Ingrid G. J., Bell, Melissa J., Ressing, Maaike E., and Wiertz, Emmanuel J. H. J.

Abstract

The Epstein-Barr virus (EBV)-encoded immune evasion protein BNLF2a inhibits the transporter associated with antigen processing (TAP), thereby downregulating HLA class I expression at the cell surface. As a consequence, recognition of EBV-infected cells by cytotoxic T cells is impaired. Here, we show that sequence polymorphism of the BNLF2a protein is observed with natural EBV isolates, with evidence for positive selection. Despite these mutations, the BNLF2a variants efficiently reduce cell surface HLA class I levels. This conservation of BNLF2a function during evolution of EBV implies an important role for the viral TAP inhibitor in preventing T cell recognition during viral infection.

Published
2012

149. Varicellovirus UL 49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP

Author

Koppers-Lalic, Danijela, Verweij, Marieke C., Lipinska, Andrea D., Wang, Ying, Quinten, Edwin, Reits, Eric A., Koch, Joachim, Loch, Sandra, Marcondes Rezende, Marisa, Daus, Franz, Bienkowska-Szewczyk, Krystyna, Osterrieder, Nikolaus, Mettenleiter, Thomas C., Heemskerk, Mirjam H. M., Tampé, Robert, Neefjes, Jacques J., Chowdhury, Shafiqul I., Ressing, Maaike E., Rijsewijk, Frans A. M., Wiertz, Emmanuel J. H. J., Koppers-Lalic, Danijela, Verweij, Marieke C., Lipinska, Andrea D., Wang, Ying, Quinten, Edwin, Reits, Eric A., Koch, Joachim, Loch, Sandra, Marcondes Rezende, Marisa, Daus, Franz, Bienkowska-Szewczyk, Krystyna, Osterrieder, Nikolaus, Mettenleiter, Thomas C., Heemskerk, Mirjam H. M., Tampé, Robert, Neefjes, Jacques J., Chowdhury, Shafiqul I., Ressing, Maaike E., Rijsewijk, Frans A. M., and Wiertz, Emmanuel J. H. J.

Abstract

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.

Published
2008

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