Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2

Gewurz, Benjamin E.; Gaudet, Rachelle; Tortorella, Domenico; Wang, Evelyn W.; Ploegh, Hidde L.; Wiley, Don C.

doi:10.1073/pnas.121172898

Cited by 139 publications

(141 citation statements)

References 51 publications

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“…Likewise, deletion of the N-terminal 90 residues also reduces the amount of TAP that coimmunoprecipitates with HCMV US6, suggesting that this region also stabilizes the interaction between HCMV US6 and TAP. Although the three-dimensional structure of HCMV US6 is unknown, by comparison with HCMV US2, whose structure has been solved, US6 has been proposed to have an immunoglobulin fold (13). Immunoglobulin domains often mediate protein-protein interactions, and it is conceivable that residues 89 to 108 may form a TAP binding surface analogous to the MHC class I binding surface formed by US2.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Dissection of the Human Cytomegalovirus Immune Evasion Protein US6

Dugan

Hewitt

2008

J Virol

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The human cytomegalovirus (HCMV) protein US6 inhibits the transporter associated with antigen processing (TAP). Since TAP transports antigenic peptides into the endoplasmic reticulum for binding to major histocompatibility class I molecules, inhibition of the transporter by HCMV US6 impairs the presentation of viral antigens to cytotoxic T lymphocytes. HCMV US6 inhibits ATP binding by TAP, hence depriving TAP of the energy source it requires for peptide translocation, yet the molecular basis for the interaction between US6 and TAP is poorly understood. In this study we demonstrate that residues 89 to 108 of the HCMV US6 luminal domain are required for TAP inhibition, whereas sequences that flank this region stabilize the binding of the viral protein to TAP. In parallel, we demonstrate that chimpanzee cytomegalovirus (CCMV) US6 binds, but does not inhibit, human TAP. The sequence of CCMV US6 differs from that of HCMV US6 in the region corresponding to residues 89 to 108 of the HCMV protein. The substitution of this region of CCMV US6 with the corresponding residues from HCMV US6 generates a chimeric protein that inhibits human TAP and provides further evidence for the pivotal role of residues 89 to 108 of HCMV US6 in the inhibition of TAP. On the basis of these observations, we propose that there is a hierarchy of interactions between HCMV US6 and TAP, in which residues 89 to 108 of HCMV US6 interact with and inhibit TAP, whereas other parts of the viral protein also bind to TAP and stabilize this inhibitory interaction.The major histocompatibility (MHC) class I antigen presentation pathway plays a central role in the immune response to viral infection. MHC class I molecules are expressed on the plasma membranes of all nucleated cells and present peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs). CTLs monitor these MHC class I molecules for peptides derived from viral proteins and kill the infected cells. The presentation of antigenic peptides to CTLs represents the end point of a complex multistep pathway. The vast majority of peptides presented by MHC class I molecules are generated by the degradation of proteins in the cytosol by the proteasome complex (38). These peptides are then translocated into the lumen of the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) (1). MHC class I molecules are assembled in the ER by a process that involves ER-resident chaperones (5). Peptide binding represents the final step of MHC class I molecule folding and is facilitated by the TAP-associated molecule tapasin, which links the nascent MHC class I molecules to TAP to form the "peptide-loading complex" (5). Only once they have bound peptides can MHC class I molecules dissociate from this complex and exit the ER for transport to the plasma membrane.TAP is a member of the ATP binding cassette (ABC) family of transporters, whose members couple ATP hydrolysis to the translocation of a broad spectrum of different substrates across cellular membranes (1,29,42). All...

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Dissection of the Human Cytomegalovirus Immune Evasion Protein US6

Dugan

Hewitt

2008

J Virol

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“…In particular, the α2 helix domain residues of RAE1γ, including Lys154, Tyr155, and Glu159, form an important contact site for both m152 and NKG2D. (33), that of the MHC-I-like UL18 with the Ig-like LIR-1 (34), and that of the Ig-like UL16 with the MHC-I-like hNKG2D ligand MICB (29). In all these complexes, the viral molecule exploits a different aspect of the host cell's ligand for interaction.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Wang¹,

Natarajan²,

Revilleza³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells are activated by engagement of the NKG2D receptor with ligands on target cells stressed by infection or tumorigenesis. Several human and rodent cytomegalovirus (CMV) immunoevasins down-regulate surface expression of NKG2D ligands. The mouse CMV MHC class I (MHC-I)-like m152/gp40 glycoprotein down-regulates retinoic acid early inducible-1 (RAE1) NKG2D ligands as well as host MHC-I. Here we describe the crystal structure of an m152/RAE1γ complex and confirm the intermolecular contacts by mutagenesis. m152 interacts in a pincer-like manner with two sites on the α1 and α2 helices of RAE1 reminiscent of the NKG2D interaction with RAE1. This structure of an MHC-I-like immunoevasin/MHC-I-like ligand complex explains the binding specificity of m152 for RAE1 and allows modeling of the interaction of m152 with classical MHC-I and of related viral immunoevasins.immune recognition | virus evasion | X-ray diffraction C ytomegaloviruses (CMV), members of the β-herpesvirus family, pathogenic in immunosuppressed or immunodeficient hosts (1), may lie dormant for many years but can cause considerable morbidity and mortality with neonatal or HIV infection or during organ transplantation (2). The large size of the CMV dsDNA genomes (as large as 250 kb), allows these viruses to dedicate many genes to viral fitness; a number of these genes thwart the host inflammatory, innate, and adaptive immune responses. Human and mouse studies emphasize the importance of natural killer (NK) and CD8 + T cells in the antiviral response, underscoring the complementary roles of innate and adaptive immunity. Of particular importance to NK-mediated immunity is NKG2D, a C-type lectin-like homodimeric glycoprotein that mediates NK cell activation on ligation by host molecules expressed at the cell surface as a result of cellular or genotoxic stress (3, 4). Human NKG2D ligands include MICA, MICB, and members of the ULBP family (4, 5), and studies suggest a complex relationship between the expression of NKG2D ligands on tumor cells, the effectiveness of immunosurveillance, and clinical prognosis (6, 7). Murine NKG2D recognizes RAE1 family members (RAE1α-ε), H60 (H60a-c), and the murine UL16-binding protein-like transcript 1 (MULT1) (8-10). Remarkably, these NKG2D ligands are related to MHC class I (MHC-I)-like molecules (11,12), and several are targets of MHC-I-like immunoevasins (3). In particular, mouse CMV (MCMV) m152/gp40 (hereafter referred to as "m152") has a dual role, downregulating cell-surface expression of RAE1 family members [but not MULT1 or H60 (13), the targets of MCMV proteins m145 and m155, respectively (14, 15)] as well as host MHC-I molecules (16)(17)(18)(19). A virus-encoded Fc receptor, m138, also controls MULT1, H60 (3), and RAE1ε (20). In vivo, MCMV deletions lacking m145, m152, m155, or m138 are defective in viral control of surface expression of MULT1, RAE1, and H60.To explore the mechanism by which MCMV MHC-I-like immunoevasins interact with and down-regulate their respective NKG2D ligands, we examined th...

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“…Further analyses indicated that ER lumenal domain of HCMV US2 is required for physiologically interaction with the α3 domain of hCD1d. Previous observation also demonstrated that ER lumenal domain of HCMV US2 is the major binding site for both MHC class Ia and class II molecules (Chevalier et al, 2002;Gewurz et al, 2001). Although hCD1d, heavy chain of MHC class Ia (HLA-A2) and MHC class II molecules (HLA-DM, HLA-DR) share only 25 to 30% of amino acid identity, ER lumenal domain of HCMV US2 still can bind to these molecules.…”

Section: Discussionmentioning

confidence: 95%

“…In addition, we identified the α3 domain of hCD1d as the major binding site of HCMV US2. Previous observation indicated that HCMV US2 binding site of heavy chain of MHC class Ia molecule (HLA-A2) is located mainly in the α3 domain of the heavy chain, which is remote from the peptide binding motif (Gewurz et al, 2001). Thus, hCD1d and MHC class Ia molecule also share the region that interacts with HCMV US2.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus (HCMV) US2 Protein Interacts with Human CD1d (hCD1d) and Down-Regulates Invariant NKT (iNKT) Cell Activity

Han

Rho

Lee

et al. 2013

Molecules and Cells

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To avoid host immune surveillance, human cytomegalovirus (HCMV) encoded endoplasmic reticulum (ER)-membrane glycoprotein US2, which interferes with antigen presenting mechanism of major histocompatibility complex (MHC) class Ia and class II molecules. However, not many attempts have been made to study the effect of HCMV US2 on the expression of MHC class Ib molecules. In this study, we examined the effect of HCMV US2 on the expression and function of human CD1d (hCD1d), which presents glycolipid antigens to invariant NKT (iNKT) cells. Our results clearly showed that the physiological interaction between ER lumenal domain of HCMV US2 and α3 domain of hCD1d was observed within ER. Compared with mature form of hCD1d, immature form of hCD1d is more susceptible to ubiquitin-dependent proteasomal degradation mediated by HCMV US2. Moreover, the ectopic expression of HCMV US2 leads to the down-modulation of iNKT cell activity without significant change of hCD1d expression. These results will advance our understanding of the function of HCMV US2 in immune evasive mechanisms against anti-viral immunity of iNKT cells.

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Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2

Cited by 139 publications

References 51 publications

Structural and Functional Dissection of the Human Cytomegalovirus Immune Evasion Protein US6

Structural and Functional Dissection of the Human Cytomegalovirus Immune Evasion Protein US6

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Human Cytomegalovirus (HCMV) US2 Protein Interacts with Human CD1d (hCD1d) and Down-Regulates Invariant NKT (iNKT) Cell Activity

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