scholarly journals Trophoblast Class I Major Histocompatibility Complex (MHC) Products Are Resistant to Rapid Degradation Imposed by the Human Cytomegalovirus (HCMV) Gene Products US2 and US11

1998 ◽  
Vol 188 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Danny J. Schust ◽  
Domenico Tortorella ◽  
Jörg Seebach ◽  
Cindy Phan ◽  
Hidde L. Ploegh
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Gene Products ◽  
Major Histocompatibility ◽  
Human Trophoblast ◽  
Heavy Chains ◽  
Histocompatibility Complex ◽  
Encode Gene

US11 and US2 encode gene products expressed early in the replicative cycle of human cytomegalovirus (HCMV), which cause dislocation of human and murine major histocompatibility complex (MHC) class I molecules from the lumen of the endoplasmic reticulum to the cytosol, where the class I heavy chains are rapidly degraded. Human histocompatibility leukocyte antigens (HLA)-C and HLA-G are uniquely resistant to the effects of both US11 and US2 in a human trophoblast cell line as well as in porcine endothelial cells stably transfected with human class I genes. Dislocation and degradation of MHC class I heavy chains do not appear to involve cell type–specific factors, as US11 and US2 are fully active in this xenogeneic model. Importantly, trophoblasts HLA-G and HLA-C possess unique characteristics that allow their escape from HCMV-associated MHC class I degradation. Trophoblast class I molecules could serve not only to block recognition by natural killer cells, but also to guide virus-specific HLA-C– and possibly HLA-G–restricted cytotoxic T-lymphocytes to their targets.

scholarly journals The Human Cytomegalovirus US8 Glycoprotein Binds to Major Histocompatibility Complex Class I Products

2002 ◽  
Vol 76 (13) ◽  
pp. 6832-6835 ◽  
Author(s):  
Rebecca S. Tirabassi ◽  
Hidde L. Ploegh
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Type I ◽  
Major Histocompatibility ◽  
Surface Distribution ◽  
Heavy Chains ◽  
Histocompatibility Complex ◽  
Lysosomal Proteins

ABSTRACT Human cytomegalovirus US8 is a type I membrane protein that partially colocalizes with cellular endosomal and lysosomal proteins. Although US8 does not have discernible effects on the processing and cell surface distribution of major histocompatibility complex (MHC) class I products, we have demonstrated that US8 binds to MHC class I heavy chains in the endoplasmic reticulum.

scholarly journals The Human Cytomegalovirus US10 Gene Product Delays Trafficking of Major Histocompatibility Complex Class I Molecules

2002 ◽  
Vol 76 (22) ◽  
pp. 11753-11756 ◽  
Author(s):  
Margo H. Furman ◽  
Neelendu Dey ◽  
Domenico Tortorella ◽  
Hidde L. Ploegh
Keyword(s):  
Endoplasmic Reticulum ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Heavy Chains ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

ABSTRACT Human cytomegalovirus (HCMV) US10 encodes a glycoprotein that binds to major histocompatibility complex (MHC) class I heavy chains. While expression of US10 delays the normal trafficking of MHC class I molecules out of the endoplasmic reticulum, US10 does not obviously facilitate or inhibit the action of two other HCMV-encoded MHC class I binding proteins, US2 and US11.

scholarly journals Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules

2008 ◽  
Vol 89 (5) ◽  
pp. 1122-1130 ◽  
Author(s):  
Kristina Oresic ◽  
Domenico Tortorella
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Major Histocompatibility Complex ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Cell Surface Expression ◽  
Major Histocompatibility ◽  
Er Quality Control ◽  
Heavy Chains ◽  
Histocompatibility Complex

Inhibition of cell-surface expression of major histocompatibility complex class I molecules by human cytomegalovirus (HCMV, a β-herpesvirus) promotes escape from recognition by CD8+ cytotoxic T cells. The HCMV US2 and US11 gene products induce class I downregulation during the early phase of HCMV infection by facilitating the degradation of class I heavy chains. The HCMV proteins promote the transport of the class I heavy chains across the endoplasmic reticulum (ER) membrane into the cytosol by a process referred to as ‘dislocation’, which is then followed by proteasome degradation. This process has striking similarities to the degradation of misfolded ER proteins mediated by ER quality control. Even though the major steps of the dislocation reaction have been characterized, the cellular proteins, specifically the ER chaperones involved in targeting class I for dislocation, have not been fully delineated. To elucidate the chaperones involved in HCMV-mediated class I dislocation, we utilized a chimeric class I heavy chain with an affinity tag at its carboxy terminus. Interestingly, US2 but not US11 continued to target the class I chimera for destruction, suggesting a structural limitation for US11-mediated degradation. Association studies in US2 cells and in cells that express a US2 mutant, US2–186HA, revealed that class I specifically interacts with calnexin, BiP and calreticulin. These findings demonstrate that US2-mediated class I destruction utilizes specific chaperones to facilitate class I dislocation. The data suggest a more general model in which the chaperones that mediate protein folding may also function during ER quality control to eliminate aberrant ER proteins.

scholarly journals Genetic Variability of the Major Histocompatibility Complex Class I Homologue Encoded by Human Cytomegalovirus Leads to Differential Binding to the Inhibitory Receptor ILT2

2005 ◽  
Vol 79 (4) ◽  
pp. 2251-2260 ◽  
Author(s):  
Mar Valés-Gómez ◽  
Mitsunori Shiroishi ◽  
Katsumi Maenaka ◽  
Hugh T. Reyburn
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Inhibitory Receptor ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Virus Isolates

ABSTRACT Human cytomegalovirus carries a gene, UL18, that is homologous to cellular major histocompatibility complex (MHC) class I genes. Like MHC class I molecules, the protein product of the UL18 gene associates with β2-microglobulin, and the stability of this complex depends on peptide loading. UL18 protein binds to ILT2 (CD85j), an inhibitory receptor present on B cells, monocytes, dendritic cells, T cells, and NK cells that also recognizes classical and nonclassical MHC molecules. These observations suggest that UL18 may play a role in viral immune evasion, but its real function is unclear. Since this molecule has similarity with polymorphic MHC proteins, we explored whether the UL18 gene varied between virus isolates. We report here that the UL18 gene varies significantly between virus isolates: amino acid substitutions were found in the predicted α1, α2, and α3 domains of the UL18 protein molecule. We also studied the ability of several variant UL18 proteins to bind to the ILT2 receptor. All of the variants tested bound to ILT2, but there were marked differences in the affinity of binding to this receptor. These differences were reflected in functional assays measuring inhibition of the cytotoxic capacity of NK cells via interaction with ILT2. In addition, the variants did not bind other members of the CD85 family. The implications of these data are discussed.

scholarly journals Human Cytomegalovirus US2 Endoplasmic Reticulum-Lumenal Domain Dictates Association with Major Histocompatibility Complex Class I in a Locus-Specific Manner

2001 ◽  
Vol 75 (11) ◽  
pp. 5197-5204 ◽  
Author(s):  
Benjamin E. Gewurz ◽  
Evelyn W. Wang ◽  
Domenico Tortorella ◽  
Danny J. Schust ◽  
Hidde L. Ploegh
Keyword(s):  
Endoplasmic Reticulum ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Peptide Sequence ◽  
Class I ◽  
Major Histocompatibility ◽  
Independent Manner ◽  
Histocompatibility Complex ◽  
Lumenal Domain

ABSTRACT The human cytomegalovirus-encoded US2 glycoprotein targets endoplasmic reticulum-resident major histocompatibility complex (MHC) class I heavy chains for rapid degradation by the proteasome. We demonstrate that the endoplasmic reticulum-lumenal domain of US2 allows tight interaction with class I molecules encoded by the HLA-A locus. Recombinant soluble US2 binds properly folded, peptide-containing recombinant HLA-A2 molecules in a peptide sequence-independent manner, consistent with US2's ability to broadly downregulate class I molecules. The physicochemical properties of the US2/MHC class I complex suggest a 1:1 stoichiometry. These results demonstrate that US2 does not require additional cellular proteins to specifically interact with soluble class I molecules. Binding of US2 does not significantly alter the conformation of class I molecules, as a soluble T-cell receptor can simultaneously recognize class I molecules associated with US2. The lumenal domain of US2 can differentiate between the products of distinct class I loci, as US2 binds several HLA-A locus products while being unable to bind recombinant HLA-B7, HLA-B27, HLA-Cw4, or HLA-E. We did not observe interaction between soluble US2 and either recombinant HLA-DR1 or recombinant HLA-DM. The substrate specificity of US2 may help explain the presence in human cytomegalovirus of multiple strategies for downregulation of MHC class I molecules.

scholarly journals Human Cytomegalovirus-Encoded Immune Modulators Partner To Downregulate Major Histocompatibility Complex Class I Molecules

2008 ◽  
Vol 83 (3) ◽  
pp. 1359-1367 ◽  
Author(s):  
Vanessa M. Noriega ◽  
Domenico Tortorella
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Immune Recognition ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Presentation Pathway ◽  
In Cells

ABSTRACT Throughout the course of natural evolution with its host, the human cytomegalovirus (HCMV) has developed a variety of strategies to avoid immune recognition and clearance. The major histocompatibility complex (MHC) class I antigen presentation pathway is a major target of the virus. HCMV encodes at least six gene products that modulate the processing of endoplasmic reticulum (ER)-resident MHC class I molecules. Here, we show that two virus-encoded proteins, US2 and US3, coordinate their functions toward the common goal of attenuating class I protein surface expression. In cells stably expressing both US2 and US3, class I molecules were almost completely downregulated from the cell surface. In addition, pulse-chase analysis revealed that the proteasome-dependent turnover of class I molecules occurs more rapidly in cells expressing both US2 and US3 than either US2 or US3 alone. The ability of US3 to retain class I molecules in the ER produces a target-rich environment for US2 to mediate the destruction of class I heavy chains. In fact, expression of US3 enhanced the association between US2 and class I molecules, thus encouraging their dislocation and degradation. This immune evasion strategy ensures that viral antigens are not presented on the cell surface during the early phase of HCMV infection, a critical time of replication and viral proliferation.

scholarly journals Human Cytomegalovirus Gene Products US2 and US11 Differ in Their Ability To Attack Major Histocompatibility Class I Heavy Chains in Dendritic Cells

2002 ◽  
Vol 76 (10) ◽  
pp. 5043-5050 ◽  
Author(s):  
Armin Rehm ◽  
Arne Engelsberg ◽  
Domenico Tortorella ◽  
Ida J. Körner ◽  
Insa Lehmann ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Human Cytomegalovirus ◽  
Cell Types ◽  
Class I ◽  
Major Histocompatibility ◽  
Heavy Chains ◽  
Histocompatibility Complex ◽  
Human Dendritic Cells

ABSTRACT Human cytomegalovirus (HCMV) encodes several proteins that inhibit major histocompatibility complex (MHC) class I-dependent antigen presentation. The HCMV products US2 and US11 are each sufficient for causing the dislocation of human and murine MHC class I heavy chains from the lumen of the endoplasmic reticulum to the cytosol, where the heavy chains are readily degraded. The apparent redundancy of US2 and US11 has been probed predominantly in cultured cell lines, where differences in their specificities were shown for murine and human MHC class I locus products. Here, we expressed US11 and US2 via adenovirus vectors and show that US11 exhibits a superior ability to degrade MHC class I molecules in primary human dendritic cells. MHC class II complexes are unaffected by US2- and US11-mediated attack. We suggest that multiple HCMV-encoded immunoevasions have evolved complementary functions in response to diverse host cell types and tissues.

scholarly journals Human Cytomegalovirus Protein pp71 Disrupts Major Histocompatibility Complex Class I Cell Surface Expression

2006 ◽  
Vol 80 (2) ◽  
pp. 951-963 ◽  
Author(s):  
Joanne Trgovcich ◽  
Colleen Cebulla ◽  
Pete Zimmerman ◽  
Daniel D. Sedmak
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Cell Surface Expression ◽  
Dependent Manner ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Presentation Pathway

ABSTRACT The human cytomegalovirus tegument protein pp71 is the product of the UL82 gene. Roles for pp71 in stimulating gene transcription, increasing infectivity of viral DNA, and the degradation of retinoblastoma family proteins have been described. Here we report a novel function for pp71 in limiting accumulation of cell surface major histocompatibility complex (MHC) class I complexes. MHC molecules were analyzed in glioblastoma cells exposed to a replication-defective adenovirus expressing UL82 (Adpp71) or after transient transfection of the UL82 gene. Accumulation of cell surface MHC class I levels diminished in a specific and dose-dependent manner after exposure to Adpp71 but not after exposure to an adenovirus expressing β-galactosidase (Adβgal). UL82 expression did not interfere with accumulation of either MHC class I heavy-chain transcript or protein, nor did UL82 expression correlate with markers of apoptosis. Rather, UL82 expression correlated with an increased proportion of MHC class I molecules exhibiting sensitivity to endoglycosidase H treatment. Finally, we show that, in cells infected with recombinant virus strain missing all of the unique short region MHC class I evasion genes, disruption of UL82 expression by short, interfering RNAs led to increased accumulation of cell surface MHC class I complexes. These findings support a novel role for HCMV pp71 in disruption of the MHC class I antigen presentation pathway.

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