Human Cytomegalovirus Encodes an MHC Class I-Like Molecule (UL142) That Functions to Inhibit NK Cell Lysis

Wills, Mark R.; Ashiru, Omodele; Reeves, Matthew B.; Okecha, Georgina; Trowsdale, John; Tomašec, Peter; Wilkinson, Gavin William Grahame; Sinclair, John; Sissons, J. G. P.

doi:10.4049/jimmunol.175.11.7457

Cited by 124 publications

(110 citation statements)

References 44 publications

(46 reference statements)

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“…Anti-hamster CD63 hybridoma was provided by Dr. M. Marsh (clone eh1C9b, generated by S. Schmid). NK primary cell lines were generated from healthy donor peripheral blood mononuclear cells as described (30).…”

Section: Methodsmentioning

confidence: 99%

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Fernández-Messina

Ashiru

Boutet

et al. 2010

Journal of Biological Chemistry

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141

166

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Tumor cells release NKG2D ligands to evade NKG2D-mediated immune surveillance. The purpose of our investigation was to explore the cellular mechanisms of release used by various members of the ULBP family. Using biochemical and cellular approaches in both transfectant systems and tumor cell lines, this paper shows that ULBP1, ULBP2, and ULBP3 are released from cells with different kinetics and by distinct mechanisms. Whereas ULBP2 is mainly shed by metalloproteases, ULBP3 is abundantly released as part of membrane vesicles known as exosomes. Interestingly, exosomal ULBP3 protein is much more potent for down-modulation of the NKG2D receptor than soluble ULBP2 protein. This is the first report showing functionally relevant differences in the biochemistry of the three members of the ULBP family and confirms that in depth study of the biochemical features of individual NKG2D ligands will be necessary to understand and manipulate the biology of these proteins for therapy.NKG2D is an activating immune receptor that can be expressed by most cytotoxic lymphocytes, including NK and CD8ϩ T cells (1). Engagement of NKG2D by its ligands leads to the activation or co-stimulation of lysis and cytokine secretion (for review, see Ref. 2). In humans, NKG2D ligands (NKG2D-L) 5 occur in two families of proteins: the polymorphic family of MHC-I-related chain A/B (MICA/B) and the multigene family of UL16-binding proteins (ULBPs, also known as RAET1A-E). In total, 10 members of this gene family have been described, of which six can be expressed as functional proteins (3). Two members of the ULBP family have a transmembrane region (ULBP4 and -5), like MICA/B, whereas the other ULBP molecules are linked to the cell membrane via glycosylphosphatidylinositol (GPI) anchors. The existence of such a large number of ligands for a single receptor is not fully understood but may reflect a differential role for different ligands in immune surveillance or an evolutionary response to selective pressures exerted by pathogens or cancer.In general, NKG2D-L are not expressed ubiquitously; instead, they are expressed in response to several types of cellular stress, such as pathogen infection (4), DNA damage (5), proteasome inhibition (6), and tumor transformation (7). For example, MICA/B are expressed in epithelial tumors, melanoma, neuroblastoma, various hematopoietic malignancies, and carcinomas; ULBPs are found in leukemia, gliomas and melanomas. An additional complication is that mRNA can be found in many cells that do not express protein suggesting post-transcriptional regulation of NKG2D-L expression (8 -10).Mice deficient in NKG2D expression show an enhanced susceptibility to the development of tumors (11). However, shedding NKG2D-L as soluble molecules allows tumor cells to evade NKG2D surveillance. Apart from reducing NKG2D-L expression on the tumor cell surface, the release of soluble molecules may also impair immune surveillance by promoting down-regulation of NKG2D (12, 13). In fact, the sustained presence in vivo of NKG2D-L down-modulates...

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Section: Methodsmentioning

confidence: 99%

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Fernández-Messina

Ashiru

Boutet

et al. 2010

Journal of Biological Chemistry

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141

166

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“…In recent studies, the UL/b' region has been demonstrated to be important for the dissemination, latency and virulence of HCMV in human hosts (9)(10)(11)(12). The UL142 ORF, located within the UL/b' region, is 921 bp in length and is predicted to encode a protein, presumably an important component in the inhibition of natural killer (NK) cell killing and the innate defense against HCMV (13).…”

Section: Introductionmentioning

confidence: 99%

Interaction between the human cytomegalovirus-encoded UL142 and cellular Snapin proteins

Liu

et al. 2014

Molecular Medicine Reports

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Abstract. Human cytomegalovirus (HCMV) infectioncan cause severe illness in immunocompromised and immunodeficient individuals. As a novel HCMV-encoded major histocompatibility complex class I-related molecule, the UL142-encoded protein (pUL142) is capable of suppressing natural killer (NK) cell recognition in the course of infection. However, no host factors that directly interact with HCMV pUL142 have been reported so far. In order to understand the interactions between HCMV pUL142 and host proteins, the current study used yeast two-hybrid screening, a GST pull-down assay and an immunofluorescence assay. A host protein, the SNARE-associated protein Snapin, was identified to directly interact and colocalize with HCMV pUL142 in transfected human embryonic kidney-293 cells. Snapin is abundantly expressed in the majority of cells and mediates the release of neurotransmitters through vesicular transport in the nervous system and vesicle fusion in non-neuronal cells. It is hypothesized that HCMV pUL142 may have an impact on the neurotransmitter release process and viral dissemination via interaction with Snapin.

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“…UL142 is a member of the UL18 gene family (36) and is predicted to have structural similarities to MHC class I, with a1 and a2 domains but no a3 domain. In addition, we previously showed that UL142 localizes to the ER and cis-Golgi (37,38) and that transduction of UL142 is sufficient to protect cells from NK cell-mediated lysis, whereas reducing UL142 translation with RNA interference during HCMV infection increases NK cellmediated cytotoxicity (37). UL142 can also downregulate the products of full-length alleles of MICA by intracellular retention in the Golgi complex (33,38).…”

mentioning

confidence: 99%

Intracellular Sequestration of the NKG2D Ligand ULBP3 by Human Cytomegalovirus

Bennett¹,

Ashiru²,

Morgan³

et al. 2010

The Journal of Immunology

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Human CMV (HCMV) encodes multiple genes that control NK cell activation and cytotoxicity. Some of these HCMV-encoded gene products modulate NK cell activity as ligands expressed at the cell surface that engage inhibitory NK cell receptors, whereas others prevent the infected cell from upregulating ligands that bind to activating NK cell receptors. A major activating NKR is the homodimeric NKG2D receptor, which has eight distinct natural ligands in humans. It was shown that HCMV is able to prevent the surface expression of five of these ligands (MIC A/B and ULBP1, 2, and 6). In this article, we show that the HCMV gene product UL142 can prevent cell surface expression of ULBP3 during infection. We further show that UL142 interacts with ULBP3 and mediates its intracellular retention in a compartment that colocalizes with markers of the cis-Golgi complex. In doing so, UL142 prevents ULBP3 trafficking to the surface and protects transfected cells from NK-mediated cytotoxicity. This is the first description of a viral gene able to mediate downregulation of ULBP3.

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Human Cytomegalovirus Encodes an MHC Class I-Like Molecule (UL142) That Functions to Inhibit NK Cell Lysis

Cited by 124 publications

References 44 publications

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Differential Mechanisms of Shedding of the Glycosylphosphatidylinositol (GPI)-anchored NKG2D Ligands

Interaction between the human cytomegalovirus-encoded UL142 and cellular Snapin proteins

Intracellular Sequestration of the NKG2D Ligand ULBP3 by Human Cytomegalovirus

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