The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation

Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02115, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2010; 207(9):2033-41. DOI: 10.1084/jem.20091793
Source: PubMed


Human cytomegalovirus (HCMV) encodes an endoplasmic reticulum (ER)-resident transmembrane glycoprotein, US10, expressed early in the replicative cycle of HCMV as part of the same cluster that encodes the known immunoevasins US2, US3, US6, and US11. We show that US10 down-regulates cell surface expression of HLA-G, but not that of classical class I MHC molecules. The unique and short cytoplasmic tail of HLA-G (RKKSSD) is essential in its role as a US10 substrate, and a tri-leucine motif in the cytoplasmic tail of US10 is responsible for down-regulation of HLA-G. Both the kinetics of HLA-G degradation and the mechanisms responsible appear to be distinct from those used by the US2 and US11 pathways, suggesting the existence of a third route of protein dislocation from the ER. We show that US10-mediated degradation of HLA-G interferes with HLA-G-mediated NK cell inhibition. Given the role of HLA-G in protecting the fetus from attack by the maternal immune system and in directing the differentiation of human dendritic cells to promote the evolution of regulatory T cells, HCMV likely targets the HLA-G-dependent axis of immune recognition no less efficiently than it interferes with classical class I MHC-restricted antigen presentation.

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Available from: Brandy Houser, Aug 19, 2014
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    • "HCMV is well known to interfere with antigen presentation on MHC-I molecules thereby evading T-cell and NK-regulated immunity (Jackson et al., 2011; Noriega et al., 2012a). Since the last reviews (Dunn et al., 2003; Mocarski, 2007), the roles of HCMV products in modulation of MHC-I expression (US2, US3, US10, US11, UL82/pp71), interference in antigen prestentation (US6) or their debilitating capacity on T-cell or NK cell recognition and function (UL16, UL18, UL141, UL142, US2) were further characterized (Wiertz et al., 1996; Cosman et al., 2001; Odeberg et al., 2003; Wills et al., 2005; Oresic et al., 2006; Dugan and Hewitt, 2008; Kim et al., 2008; Oresic and Tortorella, 2008; Ashiru et al., 2009; Muller et al., 2010; Park et al., 2010; Prod'homme et al., 2010; Noriega et al., 2012b; Penkert and Kalejta, 2012; Hesse et al., 2013; Smith et al., 2013). In addition, several gene products have a new role in immunomodulation. "
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    ABSTRACT: Human cytomegalovirus is an opportunistic double-stranded DNA virus with one of the largest viral genomes known. The 235 kB genome is divided in a unique long (UL) and a unique short (US) region which are flanked by terminal and internal repeats. The expression of HCMV genes is highly complex and involves the production of protein coding transcripts, polyadenylated long non-coding RNAs, polyadenylated anti-sense transcripts and a variety of non-polyadenylated RNAs such as microRNAs. Although the function of many of these transcripts is unknown, they are suggested to play a direct or regulatory role in the delicately orchestrated processes that ensure HCMV replication and life-long persistence. This review focuses on annotating the complete viral genome based on three sources of information. First, previous reviews were used as a template for the functional keywords to ensure continuity; second, the Uniprot database was used to further enrich the functional database; and finally, the literature was manually curated for novel functions of HCMV gene products. Novel discoveries were discussed in light of the viral life cycle. This functional annotation highlights still poorly understood regions of the genome but more importantly it can give insight in functional clusters and/or may be helpful in the analysis of future transcriptomics and proteomics studies.
    Full-text · Article · May 2014 · Frontiers in Microbiology
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    • "These conclusions are illustrated by the following examples. US10 downregulates the cell surface expression of HLA-G but not that of classical class I MHC molecules [88], because the short cytoplasmic tail of HLA-G (RKKSSD) acts as a US10 substrate. On the other hand, the US2 protein decreases levels of HLA class I molecules by supporting proteasome-mediated degradation, unlike HLA-G1, which lacks the residues essential for interaction with US2 [84]. "
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    ABSTRACT: HLA-G is a nonclassical major histocompatibility complex molecule first described at the maternal-fetal interface, on extravillous cytotrophoblasts. Its expression is restricted to some tissues in normal conditions but increases strongly in pathological conditions. The expression of this molecule has been studied in detail in cancers and is now also beginning to be described in infectious diseases. The relevance of studies on HLA-G expression lies in the well known inhibitory effect of this molecule on all cell types involved in innate and adaptive immunity, favoring escape from immune control. In this review, we summarize the features of HLA-G expression by type of infections (i.e, bacterial, viral, or parasitic) detailing the state of knowledge for each pathogenic agent. The polymorphism, the interference of viral proteins with HLA-G intracellular trafficking, and various cytokines have been described to modulate HLA-G expression during infections. We also discuss the cellular source of HLA-G, according to the type of infection and the potential role of HLA-G. New therapeutic approaches based on synthetic HLA-G-derived proteins or antibodies are emerging in mouse models of cancer or transplantation, and these new therapeutic tools may eventually prove useful for the treatment of infectious diseases.
    Full-text · Article · Apr 2014 · Research Journal of Immunology
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    • "It can be hypothesized that it might be a combination of predisposing HLA-G polymorphism in interaction with one or several other possible pathogenic factors, for example, an aberrant miRNA profile, defects in metalloproteinase activity that have been reported in preeclampsia, or the presence of certain viruses in the placenta that contribute to development of preeclampsia [96, 97]. Several studies have elucidated how human cytomegalovirus (HCMV) interferes with and downregulates HLA-G expression [98, 99]. Interestingly, a small pilot study has linked the presence of HCMV sequences and certain HLA-G alleles with increased risk of preeclampsia, and there might be some evidence for an association between CMV infection and preeclampsia [100, 101]. "
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    ABSTRACT: Pregnancy is an immunological paradox, where fetal antigens encoded by polymorphic genes inherited from the father do not provoke a maternal immune response. The fetus is not rejected as it would be theorized according to principles of tissue transplantation. A major contribution to fetal tolerance is the human leukocyte antigen (HLA)-G, a nonclassical HLA protein displaying limited polymorphism, restricted tissue distribution, and a unique alternative splice pattern. HLA-G is primarily expressed in placenta and plays multifaceted roles during pregnancy, both as a soluble and a membrane-bound molecule. Its immunomodulatory functions involve interactions with different immune cells and possibly regulation of cell migration during placental development. Recent findings include HLA-G contributions from the father and the fetus itself. Much effort has been put into clarifying the role of HLA-G during pregnancy and pregnancy complications, such as preeclampsia, recurrent spontaneous abortions, and subfertility or infertility. This review aims to clarify the multifunctional role of HLA-G in pregnancy-related disorders by focusing on genetic variation, differences in mRNA stability between HLA-G alleles, differences in HLA-G isoform expression, and possible differences in functional activity. Furthermore, we highlight important observations regarding HLA-G genetics and expression in preeclampsia that future research should address.
    Full-text · Article · Mar 2014 · Journal of Immunology Research
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