Cytomegalovirus Expresses the Chemokine Homologue vXCL1 Capable of Attracting XCR1
            <sup>+</sup>
            CD4
            <sup>−</sup>
            Dendritic Cells

Geyer, Henriette; Hartung, Evelyn; Mages, Hans W.; Weise, Christoph; Belužić, Robert; Jonjić, Stipan; Kroczek, Richard A.; Voigt, Sebastian

doi:10.1128/jvi.02330-13

Cited by 16 publications

(24 citation statements)

References 66 publications

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“…The secreted RANTES-specific chemokine receptor UL22A (also known as UL21.5) was found heavily glycosylated, as previously reported (68,69). One of the HCMV-en- coded chemokines, vCXCL1, which is thought to attract neutrophils for dissemination, was also found to be O-glycosylated, as recently shown (70,71). Four of HCMV immunoevasins, UL16, US3, US8, and US20, were identified to carry O-glycans (Fig.…”

Section: Mapping O-glycosites In Human Herpesvirusessupporting

confidence: 67%

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Bagdonaite

Nordén

Joshi

et al. 2016

Journal of Biological Chemistry

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Herpesviruses are among the most complex and widespread viruses, infection and propagation of which depend on envelope proteins. These proteins serve as mediators of cell entry as well as modulators of the immune response and are attractive vaccine targets. Although envelope proteins are known to carry glycans, little is known about the distribution, nature, and functions of these modifications. This is particularly true for O-glycans; thus we have recently developed a "bottom up" mass spectrometry-based technique for mapping O-glycosylation sites on herpes simplex virus type 1. We found wide distribution of O-glycans on herpes simplex virus type 1 glycoproteins and demonstrated that elongated O-glycans were essential for the propagation of the virus. Here, we applied our proteome-wide discovery platform for mapping O-glycosites on representative and clinically significant members of the herpesvirus family: varicella zoster virus, human cytomegalovirus, and Epstein-Barr virus. We identified a large number of O-glycosites distributed on most envelope proteins in all viruses and further demonstrated conserved patterns of O-glycans on distinct homologous proteins. Because glycosylation is highly dependent on the host cell, we tested varicella zoster virus-infected cell lysates and clinically isolated virus and found evidence of consistent O-glycosites. These results present a comprehensive view of herpesvirus O-glycosylation and point to the widespread occurrence of O-glycans in regions of envelope proteins important for virus entry, formation, and recognition by the host immune system. This knowledge enables dissection of specific functional roles of individual glycosites and, moreover, provides a framework for design of glycoprotein vaccines with representative glycosylation.

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Section: Mapping O-glycosites In Human Herpesvirusessupporting

confidence: 67%

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Bagdonaite

Nordén

Joshi

et al. 2016

Journal of Biological Chemistry

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“…Taken together, this work further established unique roles for the different structural states of XCL1 in anti-HIV activity. In addition to HIV, other viruses such as herpesviruses have been shown to disrupt/exploit XCL1-XCR1 signaling through the production of XCL1 and XCR1 mimics 18, 23, 24 . It is reasonable to speculate that the conformational states of XCL1 may be implicated in other pathogenic pathways.…”

Section: Resultsmentioning

confidence: 99%

Engineering Metamorphic Chemokine Lymphotactin/XCL1 into the GAG-Binding, HIV-Inhibitory Dimer Conformation

et al. 2015

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Unlike other chemokines, XCL1 undergoes a distinct metamorphic interconversion between a canonical monomeric chemokine fold and a unique β-sandwich dimer. The monomeric conformation binds and activates the receptor XCR1, while the dimer binds extracellular matrix glycosaminoglycans and has been associated with anti-human immunodeficiency virus (HIV) activity. Functional studies of WT-XCL1 are complex as both conformations are populated in solution. To overcome this limitation, we engineered a stabilized dimeric variant of XCL1 designated CC5. This variant features a neo-disulfide bond (A46C-A49C) that prevents structural interconversion by locking the chemokine into the β-sandwich dimeric conformation, as demonstrated by NMR structural analysis and hydrogen-deuterium exchange experiments. Functional studies analyzing glycosaminoglycan binding demonstrate that CC5 binds with high affinity to heparin. In addition, CC5 exhibits potent inhibition of HIV-1 activity in primary peripheral blood mononuclear cells (PBMCs), demonstrating the importance of the dimer in blocking viral infection. Conformational variants like CC5 are valuable tools for elucidating the biological relevance of the XCL1 native-state interconversion and will assist in future anti-viral and functional studies.

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“…Recently, the first virally encoded C chemokine homolog, vXCL1, was identified in the English strain of RCMV, ORF e156.5 [109]. vXCL1 displays very high amino acid sequence identity with its human (46%), mouse (58%), and rat (64%) host counterparts and like XCL1, binds specifically to XCR1expressing cells [109]. In mouse, cellular Xcr1 expression is restricted to a splenic subset of CD8 + DCs that migrate toward Xcl1 [110].…”

Section: Vxcl1 (E1565)mentioning

confidence: 99%

“…In rat, splenic CD4 2 DCs are thought to be equivalent to mouse CD8 + DCs [112]. Accordingly, it has been reported that vXCL1 is a chemoattractant for CD4 2 DCs but not for other DC subsets, with a potency and efficacy similar to that of rat Xcl1 [109]. To date, there are no data defining the clinical, immunologic, and virologic functions of vXCL1 in the context of RCMV infection in vivo.…”

Section: Vxcl1 (E1565)mentioning

confidence: 99%

Chemokines encoded by herpesviruses

Pontejo

Murphy

2017

Journal of Leukocyte Biology

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Viruses use diverse strategies to elude the immune system, including copying and repurposing host cytokine and cytokine receptor genes. For herpesviruses, the chemokine system of chemotactic cytokines and receptors is a common source of copied genes. Here, we review the current state of knowledge about herpesvirus-encoded chemokines and discuss their possible roles in viral pathogenesis, as well as their clinical potential as novel anti-inflammatory agents or targets for new antiviral strategies.

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Cytomegalovirus Expresses the Chemokine Homologue vXCL1 Capable of Attracting XCR1 ⁺ CD4 ⁻ Dendritic Cells

Cited by 16 publications

References 66 publications

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Engineering Metamorphic Chemokine Lymphotactin/XCL1 into the GAG-Binding, HIV-Inhibitory Dimer Conformation

Chemokines encoded by herpesviruses

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Cytomegalovirus Expresses the Chemokine Homologue vXCL1 Capable of Attracting XCR1 + CD4 − Dendritic Cells

Cited by 16 publications

References 66 publications

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Engineering Metamorphic Chemokine Lymphotactin/XCL1 into the GAG-Binding, HIV-Inhibitory Dimer Conformation

Chemokines encoded by herpesviruses

Contact Info

Product

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Cytomegalovirus Expresses the Chemokine Homologue vXCL1 Capable of Attracting XCR1 ⁺ CD4 ⁻ Dendritic Cells