Human cytomegalovirus UL18 utilizes US6 for evading the NK and T-cell responses.
Human cytomegalovirus (HCMV) US6 glycoprotein inhibits TAP function, resulting in down-regulation of MHC class I molecules at the cell surface. Cells lacking MHC class I molecules are susceptible to NK cell lysis. HCMV expresses UL18, a MHC class I homolog that functions as a surrogate to prevent host cell lysis. Despite a high level of sequence and structural homology between UL18 and MHC class I molecules, surface expression of MHC class I, but not UL18, is down regulated by US6. Here, we describe a mechanism of action by which HCMV UL18 avoids attack by the self-derived TAP inhibitor US6. UL18 abrogates US6 inhibition of ATP binding by TAP and, thereby, restores TAP-mediated peptide translocation. In addition, UL18 together with US6 interferes with the physical association between MHC class I molecules and TAP that is required for optimal peptide loading. Thus, regardless of the recovery of TAP function, surface expression of MHC class I molecules remains decreased. UL18 represents a unique immune evasion protein that has evolved to evade both the NK and the T cell immune responses.
Kim
Youngkyun
Y
National Creative Research Initiatives Center for Antigen Presentation, Department of Biological Sciences, Seoul National University, Seoul, Korea.
Park
Boyoun
B
Cho
Sunglim
S
Shin
Jinwook
J
Cho
Kwangmin
K
Jun
Youngsoo
Y
Ahn
Kwangseog
K
D036022:Capsid Proteins / Q000276:immunology* / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D016601:RNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology* / Q000378:metabolism
D036022:Capsid Proteins; D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D010455:Peptides; D016601:RNA-Binding Proteins; C432877:US6 protein, Human cytomegalovirus; C079750:VP23 protein, Human herpesvirus 1; D014764:Viral Proteins; C107762:tapasin