Oxysterol‐EBI2 signaling in immune regulation and viral infection

Abstract

The seven transmembrane G protein-coupled receptor Epstein-Barr virus (EBV) induced gene 2 (EBI2; also known as GPR183) was identified in 1993 on the basis of its substantial upregulation in EBV-infected cells. It is primarily expressed in lymphoid cells; most abundantly in B cells. EBI2 is central for the positioning of B cells within the lymphoid organs, a process that is regulated in part by a chemotactic gradient formed by the endogenous lipid agonists, and in part by a fine-tuned regulation of EBI2 cell surface expression. The most potent endogenous EBI2 agonist is 7α, 25-dihydroxyxcholesterol (7α,25-OHC), yet many structurally related oxysterols can bind to an EBI2 pocket that is defined by the upper parts of the transmembrane helices and extracellular receptor regions. EBI2 signals via Gαi, as well as via G protein-independent pathways like β-arrestin recruitment. The concerted action of these pathways leads to cell migration. By genetically interfering with its up- and downregulation, EBI2 was also recently shown to induce cell proliferation, an action that could be inhibited by small molecule antagonists. Here, we focus on the oxysterol–EBI2 axis in immune control, including its role in the EBV life cycle. We also summarize the structural and functional properties of EBI2 interaction with oxysterol agonists and small molecule antagonists and discuss EBI2 as therapeutic target for diseases of the immune system.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…Another theory describes the potential for EBV to preferentially drive proinflammatory B cell cytokine responses [e.g., tumor necrosis factor (TNF), lymphotoxin (LT), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression] [40,41] and interfere with the downregulatory function of IL-10. Another theory based on the ability of EBV to induce expression of EBV-induced G protein-coupled receptor 2 (EBI2/ GPR183) [42][43][44][45] supports, in part, migration of autoreactive T cells and EBV-infected B cells into the CNS.…”

Biased agonism and allosteric modulation of G protein‐coupled receptor 183 – a 7TM receptor also known as Epstein–Barr virus‐induced gene 2

“…Structure and expression profile of human WT and mutated EBI2 receptor. (A) Helical wheel model with residues involved in agonist binding shown as light pink (Tyr 112 , Tyr 116 and Tyr 260 ) and light blue (Arg 87 )(Benned‐Jensen et al, ; Zhang et al, ; Daugvilaite et al, ) The main residue in this study, Asn 114 in position III:11/3.35, shown in yellow, was mutated to alanine (N114A). (B) TM helices TM‐II to TM‐VII indicated and organized in an anticlockwise direction (TM‐I was omitted for clarity).…”

“…However, G protein‐independent activation via β‐arrestin recruitment has also been demonstrated (Hannedouche et al, ; Liu et al, ; Benned‐Jensen et al, ). Among the oxysterol ligands identified, the most potent one, 7α,25‐dihydroxycholesterol (7α,25‐OHC), displays potencies ranging from 200 nM in β‐arrestin recruitment to 0.1 nM in GTP γ S binding (Daugvilaite et al, ). The closest human homologues of EBI2 are GPR17 and GPR18, yet these three receptors share very little functional overlap except for the overall lipid nature of the endogenous ligands (Kohno et al, ; Benned‐Jensen and Rosenkilde, ; Nørregaard et al, ).…”

High‑cholesterol diet results in elevated amyloid‑β and oxysterols in rats

“…To gain insight into the association between cholesterol and cognitive decline, the present study focused on the oxidized derivatives of cholesterol, including 27-hydroxycholesterol (OHC), 24S-OHC, 7α-OHC and 7β-OHC. It has been reported that elevated oxysterols in the plasma have cytotoxic and pro-apoptotic effects on neurons (9,10). Furthermore, oxysterols can pass through the blood brain barrier into the central nervous system (11) and increase Aβ production via upregulation of the amyloidogenic pathway (12).…”