The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation

Lehner, Paul J.; Karttunen, Jaana T.; Wilkinson, Gavin William Grahame; Cresswell, Peter

doi:10.1073/pnas.94.13.6904

Cited by 255 publications

(169 citation statements)

References 49 publications

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“…Although the hCMV US gene products US2, 3, 6, and 11 can reduce the MHC class I antigen expression level on the cell surface after a viral infection by various mechanisms [22][23][24][25][26], it is not known if US gene transfection affects the MHC class I expression on stem cells. Therefore, this study tested MHC class I expression on US genetransfected HB1.F3 cells or mock-transfected cells 48 h after the IFN-c treatment using immunofluorescence analysis.…”

Section: Modification Of Mhc Class I Expression Of Hb1f3 Cells With mentioning

confidence: 99%

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Down-regulation of MHC class I expression in human neuronal stem cells using viral stealth mechanism

Lee

Kim

Cho

et al. 2005

Biochemical and Biophysical Research Communications

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Section: Modification Of Mhc Class I Expression Of Hb1f3 Cells With mentioning

confidence: 99%

“…Its gene products, US2, US3, US6, and US11, can independently reduce MHC class I expression on the cell surface [22][23][24][25][26].…”

mentioning

confidence: 99%

Down-regulation of MHC class I expression in human neuronal stem cells using viral stealth mechanism

Lee

Kim

Cho

et al. 2005

Biochemical and Biophysical Research Communications

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“…By inhibiting TAP, HCMV US6 decreases cell surface expression of MHC class I molecules and hence reduces CTL killing (2,15,27). HCMV US6 does not block peptide binding by TAP but inhibits ATP binding and hydrolysis by the transporter (2,15,16,26,27). In effect, HCMV US6 starves TAP of the energy source that it requires for peptide translocation.…”

mentioning

confidence: 99%

“…Human cytomegalovirus (HCMV) encodes the protein US6, which is an ER-localized type I integral membrane glycoprotein that inhibits peptide translocation by TAP (2,15,27). By inhibiting TAP, HCMV US6 decreases cell surface expression of MHC class I molecules and hence reduces CTL killing (2,15,27).…”

mentioning

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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“…US6, a recombinant soluble version of product of a human cytomegalovirus immune-evasion gene, blocks peptide translocation by TAP. The MHC-I of human cells expressed US6 dramatically reduced (11)(12)(13). To evade the host's immune response, herpes simplex virus employs the immediate early gene product ICP47 (IE12) to suppress antigen presentation to CTLs by inhibition of TAP (14).…”

Section: The Classical Tap-dependent Mhc-i Antigen Processing and Prementioning

confidence: 99%

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Liu

Gao

2008

Cell Mol Immunol

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The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation

Cited by 255 publications

References 49 publications

Down-regulation of MHC class I expression in human neuronal stem cells using viral stealth mechanism

Down-regulation of MHC class I expression in human neuronal stem cells using viral stealth mechanism

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

Manipulation of MHC-I/TCR Interaction for Immune Therapy

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