Molecular Characterization of Oxysterol Binding to the Epstein-Barr Virus-induced Gene 2 (GPR183)

Benned-Jensen, Tau; Norn, Christoffer; Laurent, Stéphane; Madsen, Christian; Larsen, Hjalte M.; Arfelt, Kristine Niss; Wolf, Romain M.; Frimurer, Thomas M.; Sailer, Andreas W.; Rosenkilde, Mette M.

doi:10.1074/jbc.m112.387894

Cited by 46 publications

(57 citation statements)

References 46 publications

(81 reference statements)

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“…Significant progress has been made in elucidating the functional significance of oxysterol-induced B- and T-cell migration in lymphoid organs [29,30,50–52]. It is now widely accepted that EBI2-mediated chemotaxis represents an important molecular mechanism directing follicular B cell migration and localization.…”

Section: Discussionmentioning

confidence: 99%

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On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment

Eibinger

Fauler

Bernhart

et al. 2013

Experimental Cell Research

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Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and is invariably fatal to affected patients. Oxysterols belong to a class of bioactive lipids that are implicated in neurological disease and are associated with various types of cancer. Here, we investigated expression and transcriptional regulation of cholesterol 25-hydroxylase (CH25H) in human U87MG and GM133 glioblastoma cell lines. We demonstrate that in both cell lines transcription and translation of CH25H are increased in response to TNFα and IL1β. In parallel, both cell lines upregulate 25-hydroxycholesterol (25-OHC) synthesis and secretion to levels comparable to bone marrow-derived mouse macrophages under inflammatory conditions. To determine whether 25-OHC acts as chemoattractant for tumor-associated macrophages, the human THP-1 monoblastic leukemia cell line was treated with varying amounts of the oxysterol. Experiments revealed that 25-OHC and lipid extracts isolated from GM133-conditioned medium (containing 7-fold higher 25-OHC concentrations than U87MG medium) induce chemotactic migration of THP-1 cells. Of note, 25-OHC also induced the migration of primary human peripheral blood monocytes. In response to exogenously added 25-OHC, THP-1 cells reorganized intermediate filament-associated vimentin to more cortical and polarized structures. Chemotactic migration of monocytes in response to 25-OHC was pertussis toxin-sensitive, indicating the involvement of G protein-coupled receptors. Using RNA interference we demonstrated that G protein–coupled receptor 183 (EBI2) contributes to 25-OHC-mediated chemotactic migration of THP-1 cells. These in vitro data indicate that GBM-derived and secreted 25-OHC may be involved in the recruitment of immune-competent cells to a tumor via EBI2.

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Section: Discussionmentioning

confidence: 99%

“…6), PTX suppressed 7α,25-OHC stimulated and EBI2-mediated binding of GTP [30]. However, PTX-insensitive ERK activation in response to EBI2 engagement was also reported [52]. The functional potency of different oxysterols towards EBI2 is 7α,25-OHC>7α,27-OHC>7α–OHC>25-OHC>27-OHC [50].…”

Section: Discussionmentioning

confidence: 99%

On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment

Eibinger

Fauler

Bernhart

et al. 2013

Experimental Cell Research

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“…Oxysterol activation of EBI2/GPR183 (Epstein Barr Virus-induced Molecule 2), a class A GPCR ( G - p rotein c oupled r eceptor), is triggered in immune cells by binding of 7α-25- or 7α-27- hydroxycholesterol (7α-25-OHC, 7α-27-OHC) to a pocket located within the external half of the membrane-spanning heptahelical bundle (Benned-Jensen et al, 2012; Zhang et al, 2012). A similar ligand-binding pocket exists in Smo, and mutations in this region disrupt the binding of cyclopamine, of its synthetic mimics, and of certain agonists (Buonamici et al, 2010; Dijkgraaf et al, 2011).…”

Section: An Intact Crd Is Required For Smo Activation By Oxysterolsmentioning

confidence: 99%

Hedgehog Pathway Modulation by Multiple Lipid Binding Sites on the Smoothened Effector of Signal Response

et al. 2013

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Summary Hedgehog (Hh) signaling during development and in postembryonic tissues requires activation of the 7TM oncoprotein Smoothened (Smo), by mechanisms that may involve endogenous lipidic modulators. Exogenous Smo ligands previously identified include the plant sterol cyclopamine (and its therapeutically useful synthetic mimics) and hydroxylated cholesterol derivatives (oxysterols); Smo is also highly sensitive to cellular sterol levels. The relationships between these effects are unclear because the relevant Smo structural determinants are unknown. We identify the conserved extracellular cysteine rich domain (CRD) as the site of action for oxysterols on Smo, involving residues structurally analogous to those contacting the Wnt lipid adduct in the homologous Frizzled CRD; this modulatory effect is distinct from that of cyclopamine mimics, from Hh-mediated regulation, and from the permissive action of cellular sterol pools. These results imply that Hh pathway activity is sensitive to lipid binding at several Smo sites, suggesting mechanisms for tuning by multiple physiological inputs.

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“…Much has been learned about the biology and pharmacology of EBI2 in the past 2 years. Thus, both the endogenous agonist [5,6], the cellular producers of this agonist [7] and the molecular pharmacology of 7α,25‐OHC, the most potent agonist, [9,10] have all been characterized within this period. In addition, just prior to the deorphanization, we presented a non‐peptide compound, GSK682753A, which inhibited the apparent constitutive activity of EBI2 [16].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the main oxysterol generating cells within the lymphoid tissue were recently shown to be of stromal origin and these are required for efficient T cell‐dependent plasma cell responses [7]. Moreover, we [8,9] and others [10] identified residues critical for oxysterol binding to EBI2 showing that the main anchor points are found in TM‐II, ‐III, ‐VI and ECL2 of which several are located in the minor binding pocket [11].…”

Section: Introductionmentioning

confidence: 99%

Small molecule antagonism of oxysterol‐induced Epstein–Barr virus induced gene 2 (EBI2) activation

Benned-Jensen¹,

Madsen²,

Arfelt³

et al. 2013

FEBS Open Bio

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The Epstein–Barr virus induced gene 2 (EBI2) was recently identified as the first oxysterol-activated 7TM receptor. EBI2 is essential for B cell trafficking within lymphoid tissues and thus the humoral immune response in general. Here we characterize the antagonism of the non-peptide molecule GSK682753A, which blocks oxysterol-induced G-protein activation, β-arrestin recruitment and B-cell chemotaxis. We furthermore demonstrate that activation triggers pertussis toxin-sensitive MAP kinase phosphorylation, which is also inhibited by GSK682753A. Thus, EBI2 signalling in B cells mediates key phenotypic functions via signalling pathways amenable to manipulation providing additional therapeutic options for inhibiting EBI2 activity.

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Molecular Characterization of Oxysterol Binding to the Epstein-Barr Virus-induced Gene 2 (GPR183)

Cited by 46 publications

References 46 publications

On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment

On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment

Hedgehog Pathway Modulation by Multiple Lipid Binding Sites on the Smoothened Effector of Signal Response

Small molecule antagonism of oxysterol‐induced Epstein–Barr virus induced gene 2 (EBI2) activation

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