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

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

doi:10.4049/jimmunol.1400964

Cited by 32 publications

(46 citation statements)

References 56 publications

(80 reference statements)

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“…Secondly, another viral protein–CPXV12 –abrogates ER peptide loading and dissociation of MHC class I molecules from transporter associated with antigen processing (TAP) [42]. CPXV12 prevents peptide transport by inhibiting ATP binding to the nucleotide binding domains (NDBs) of TAP [43]. VACV inhibits MHC II expression on DCs and blocks presentation of antigenic peptides in MHC class II molecules by viral A35 protein, which localizes to endosomes [18,19].…”

Section: Discussionmentioning

confidence: 99%

Functional paralysis of GM-CSF–derived bone marrow cells productively infected with ectromelia virus

et al. 2017

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Ectromelia virus (ECTV) is an orthopoxvirus responsible for mousepox, a lethal disease of certain strains of mice that is similar to smallpox in humans, caused by variola virus (VARV). ECTV, similar to VARV, exhibits a narrow host range and has co-evolved with its natural host. Consequently, ECTV employs sophisticated and host-specific strategies to control the immune cells that are important for induction of antiviral immune response. In the present study we investigated the influence of ECTV infection on immune functions of murine GM-CSF–derived bone marrow cells (GM-BM), comprised of conventional dendritic cells (cDCs) and macrophages. Our results showed for the first time that ECTV is able to replicate productively in GM-BM and severely impaired their innate and adaptive immune functions. Infected GM-BM exhibited dramatic changes in morphology and increased apoptosis during the late stages of infection. Moreover, GM-BM cells were unable to uptake and process antigen, reach full maturity and mount a proinflammatory response. Inhibition of cytokine/chemokine response may result from the alteration of nuclear translocation of NF-κB, IRF3 and IRF7 transcription factors and down-regulation of many genes involved in TLR, RLR, NLR and type I IFN signaling pathways. Consequently, GM-BM show inability to stimulate proliferation of purified allogeneic CD4+ T cells in a primary mixed leukocyte reaction (MLR). Taken together, our data clearly indicate that ECTV induces immunosuppressive mechanisms in GM-BM leading to their functional paralysis, thus compromising their ability to initiate downstream T-cell activation events.

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Section: Discussionmentioning

confidence: 99%

Functional paralysis of GM-CSF–derived bone marrow cells productively infected with ectromelia virus

et al. 2017

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“…In contrast, the recently discovered and so far only known poxviral TAP inhibitor CPXV012 (Alzhanova et al, 2009;Byun et al, 2009) inhibits peptide transport by preventing ATP binding to TAP1 and TAP2 but not high-affinity peptide binding (Lin et al, 2014;Luteijn et al, 2014). CPXV012 is a 69-aa type II membrane protein consisting of a short N-terminal cytosolic region, a transmembrane helix, and a short ER-lumenal tail.…”

Section: Viral Immune Evasionmentioning

confidence: 99%

“…CPXV012 is a 69-aa type II membrane protein consisting of a short N-terminal cytosolic region, a transmembrane helix, and a short ER-lumenal tail. The C-terminal region is sufficient for TAP inhibition; however, the transmembrane and cytosolic regions increase the inhibition effect by providing an additional interaction site for TAP (Lin et al, 2014;Luteijn et al, 2014). Notably, the C-terminal region of CPXV012 evolved from a genomic frameshift mutation in the extended ER-lumenal tail of homologous inactive CPXV012 variants as detected for D10L (Alzhanova et al, 2009;Carroll et al, 2011).…”

Section: Viral Immune Evasionmentioning

confidence: 99%

The transporter associated with antigen processing: a key player in adaptive immunity

Eggensperger

Tampé²

2015

Biological Chemistry

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Abstract:The adaptive immune system co-evolved with sophisticated pathways of antigen processing for efficient clearance of viral infections and malignant transformation. Antigenic peptides are primarily generated by proteasomal degradation and translocated into the lumen of the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). In the ER, peptides are loaded onto major histocompatibility complex I (MHC I) molecules orchestrated by a multisubunit peptide-loading complex (PLC). Peptide-MHC I complexes are targeted to the cell surface for antigen presentation to cytotoxic T cells, which eventually leads to the elimination of virally infected or malignantly transformed cells. Here, we review MHC I mediated antigen processing with a primary focus on the function and structural organization of the heterodimeric ATP-binding cassette (ABC) transporter TAP1/2. We discuss recent data on the molecular transport mechanism of the antigen translocation complex with respect to structural and biochemical information of other ABC exporters. We further summarize how TAP provides a scaffold for the assembly of the macromolecular PLC, thereby coupling peptide translocation with MHC I loading. TAP inhibition by distinct viral evasins highlights the important role of TAP in adaptive immunity.

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“…Recently, the mechanism of action of the cowpox virus‐derived TAP inhibitor CPXV012 was elucidated . CPXV012 is a type II transmembrane protein that localizes to the ER.…”

Section: Introductionmentioning

confidence: 99%

“…Here, it directly binds to TAP and blocks peptide transport by steric interference with ATP binding. The ER‐luminal domain of CPXV012 is necessary and sufficient for this inhibitory effect …”

Section: Introductionmentioning

confidence: 99%

Endocytosed soluble cowpox virus protein CPXV012 inhibits antigen cross‐presentation in human monocyte‐derived dendritic cells

et al. 2018

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Viruses may interfere with the MHC class I antigen presentation pathway in order to avoid CD8 T cell-mediated immunity. A key target within this pathway is the peptide transporter TAP. This transporter plays a central role in MHC class I-mediated peptide presentation of endogenous antigens. In addition, TAP plays a role in antigen cross-presentation of exogenously derived antigens by dendritic cells (DCs). In this study, a soluble form of the cowpox virus TAP inhibitor CPXV012 is synthesized for exogenous delivery into the antigen cross-presentation route of human monocyte-derived (mo)DCs. We show that soluble CPXV012 localizes to TAP compartments that carry internalized antigen and is a potent inhibitor of antigen cross-presentation. CPXV012 stimulates the prolonged deposition of antigen fragments in storage compartments of moDCs, as a result of reduced endosomal acidification and reduced antigen proteolysis when soluble CPXV012 is present. Thus, a dual function can be proposed for CPXV012: inhibition of TAP-mediated peptide transport and inhibition of endosomal antigen degradation. We propose this second function for soluble CPXV012 can serve to interfere with antigen cross-presentation in a peptide transport-independent manner.

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

Cited by 32 publications

References 56 publications

Functional paralysis of GM-CSF–derived bone marrow cells productively infected with ectromelia virus

Functional paralysis of GM-CSF–derived bone marrow cells productively infected with ectromelia virus

The transporter associated with antigen processing: a key player in adaptive immunity

Endocytosed soluble cowpox virus protein CPXV012 inhibits antigen cross‐presentation in human monocyte‐derived dendritic cells

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