The MHC class I homolog encoded by human cytomegalovirus binds endogenous peptides

Fahnestock, Margaret; Johnson, Jennifer L.; Feldman, R. M. Renny; Neveu, John M.; Lane, William S.; Björkman, Pamela J.

doi:10.1016/1074-7613(95)90129-9

Cited by 129 publications

(88 citation statements)

References 29 publications

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“…UL18 contains a cytoplasmic tail, a transmembrane region and three extracellular domains (a1, a2 and a3) with approximately 25% homology to classical HLA-I [7]. It associates with b 2 -microglobulin (b2m) [16] and binds peptides [17], but unlike HLA-I it has 13 potential N-linked glycosylation sites [7]. To date, the only molecule shown to be able to bind to UL18 is the inhibitory receptor LIR-1/ILT2/CD85j [11,18], which will be referred to as leukocyte Ig-like receptor (LIR)-1 in the rest of this report.…”

Section: Molecular Immunologymentioning

confidence: 99%

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

et al. 2006

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Human cytomegalovirus (HCMV) down-regulates cell surface expression of HLA class I molecules (HLA-I). UL18, an HCMV-encoded HLA-I homologue, has been proposed to protect virus-infected cells against NK cell recognition by engaging the inhibitory receptor leukocyte Ig-like receptor (LIR)-1, which also binds a broad spectrum of HLA-I alleles, including HLA-G1. Because genetic and biological differences exist among HCMV strains, we characterized laboratory (AD169) and clinical (4636, 13B, 109B) strain-derived UL18 proteins. Compared to the known AD169-derived UL18, mutations were found in clinical strain-derived UL18. They were clustered in the a3 domain (13B), previously shown to be critical for LIR-1 binding, or in the a1 domain (4636). In cytotoxicity assays, pretreatment of LIR-1 + NKL with soluble 4636-UL18 completely abolished LIR-1-dependent protection from NK lysis, conferred by the expression of HLA-G1 on target cells (721.221-HLA-G1 + ). Similarly, flow cytometry, Biacore and ELISA experiments showed 4636-UL18 and 13B-UL18 to have the strongest binding capacity to LIR-1. Our results suggest the importance of two independent UL18 regions for LIR-1 binding, one localized on the tip of the a3 domain, and another composed of two loops that emerge from the a1 domain. Strain variations in these domains may result in different UL18-mediated effects on LIR-1 + cells during the course of HCMV infection.

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Section: Molecular Immunologymentioning

confidence: 99%

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

et al. 2006

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“…It associates with the class I MHC light chain, ␤2-microglobulin (␤2m) (12), and with endogenous peptides derived from cytoplasmic proteins that resemble those bound to host class I proteins (13). Peptide binding renders UL18 unique among viral MHC homologs and unusual among host MHC homologs.…”

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confidence: 99%

Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor

Yang

Björkman

2008

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

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UL18 is a human cytomegalovirus class I MHC (MHCI) homolog that binds the host inhibitory receptor LIR-1 and the only known viral MHC homolog that presents peptides. The 2.2-Å structure of a LIR-1/UL18/peptide complex reveals increased contacts and optimal surface complementarity in the LIR-1/UL18 interface compared with LIR/MHCI interfaces, resulting in a >1,000-fold higher affinity. Despite sharing only Ϸ25% sequence identity, UL18's structure and peptide binding are surprisingly similar to host MHCI. The crystal structure suggests that most of the UL18 surface, except where LIR-1 and the host-derived light chain bind, is covered by carbohydrates attached to 13 potential N-glycosylation sites, thereby preventing access to bound peptide and association with most MHCI-binding proteins. The LIR-1/UL18 structure demonstrates how a viral protein evolves from its host ancestor to impede unwanted interactions while preserving and improving its receptor-binding site.cytomegalovirus ͉ immune evasion ͉ LIR-1 ͉ x-ray crystallography H uman cytomegalovirus (HCMV) is prevalent among all human populations, infecting 70-90% of adults (1). HCMV infection is usually asymptomatic in immunocompetent individuals, but the virus causes a latent infection that can be reactivated during immune suppression. To maintain persistence in the presence of a primed immune system, HCMV has developed mechanisms to subvert the host immune response (2). One strategy is to downregulate cell surface expression of host class I MHC molecules, thereby allowing HCMV-infected cells to avoid recognition by virus-specific cytotoxic T cells. However, cells that lack surface class I MHC molecules are susceptible to lysis by natural killer (NK) cells (3). NK cells express both activating receptors and inhibitory receptors, many of which recognize class I MHC molecules (4). Stimulation of the activating receptors leads to lysis of target cells when expression of class I MHC proteins is down-regulated (5); however, clinical isolates of HCMV can evade NK lysis (6) by down-regulation (7) or inhibition (8) of the activating ligands for NK cells; up-regulation of HLA-E (9), which binds the NK cell inhibitory receptor NKG2A/CD94; and potentially through the expression of two virally encoded class I MHC homologs, UL142 (10) and UL18 (11).UL18 is a heavily glycosylated transmembrane protein that shares Ϸ25% sequence identity with class I MHC molecules (11). It associates with the class I MHC light chain, ␤2-microglobulin (␤2m) (12), and with endogenous peptides derived from cytoplasmic proteins that resemble those bound to host class I proteins (13). Peptide binding renders UL18 unique among viral MHC homologs and unusual among host MHC homologs. The role of UL18 in NK cell recognition is controversial; it has been reported to inhibit NK-cell-mediated lysis in some experimental conditions but not others (14).The only host receptor identified for UL18 is LIR-1 (15) (also known as ILT2, CD85j, or LILRB1) (16). LIR-1 is expressed on most or all monocytes, dendritic and...

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“…UL18 displays a structural homology with HLA class I molecules as well as a significant amino acid identity (11). It associates with ␤ 2 -microglobulin (12), and the stability of the trimeric complex depends on the presence of a loaded peptide (13). It is a late HCMV Ag in that its transcription occurs from 54 to at least 120 h postinfection (14) and is not essential for HCMV replication (15).…”

mentioning

confidence: 99%

Human Cytomegalovirus Regulates Surface Expression of the Viral Protein UL18 by Means of Two Motifs Present in the Cytoplasmic Tail

Maffei¹,

Ghiotto²,

Occhino³

et al. 2008

The Journal of Immunology

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UL18 is a trans-membrane viral protein expressed on human cytomegalovirus (HCMV)-infected cells, and its surface expression determines the interaction of infected cells with lymphocytes expressing the CD85j (LIR-1/ILT2) receptor. We previously showed that the UL18–CD85j interaction elicits activation of T lymphocytes. However, in in vitro cell models UL18 displays mostly undetectable surface expression. Thus, we asked how surface expression of UL18 is regulated. Domain-swapping experiments and construction of specific mutants demonstrated that two motifs on its cytoplasmic tail, homologous to YXXΦ and KKXX consensus sequences, respectively, are responsible for impairing UL18 surface expression. However, the presence of the whole HCMV genome, granted by HCMV infection of human fibroblasts, restored surface expression of either UL18 or chimeric proteins carrying the UL18 cytoplasmic tail, starting from the third day after infection. It is of note that the two motifs responsible for cytoplasmic retention are identical in all 17 HCMV strains examined. We disclosed a control mechanism used by the HCMV to regulate the availability of UL18 on the infected-cell surface to allow interaction with its ligand on T and NK cells.

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The MHC class I homolog encoded by human cytomegalovirus binds endogenous peptides

Cited by 129 publications

References 29 publications

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

Spontaneous mutations in the human CMV HLA class I homologue UL18 affect its binding to the inhibitory receptor LIR‐1/ILT2/CD85j

Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor

Human Cytomegalovirus Regulates Surface Expression of the Viral Protein UL18 by Means of Two Motifs Present in the Cytoplasmic Tail

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