Distinct Roles of Extracellular Domains in the Epstein-Barr Virus-Encoded BILF1 Receptor for Signaling and Major Histocompatibility Complex Class I Downregulation

Abstract

G protein-coupled receptors constitute the largest family of membrane proteins. As targets of >30% of the FDA-approved drugs, they are valuable for drug discovery. The receptor is composed of seven membrane-spanning helices and intracellular and extracellular domains. BILF1 is a receptor encoded by Epstein-Barr virus (EBV), which evades the host immune system by various strategies. BILF1 facilitates the virus immune evasion by downregulating MHC class I and is capable of inducing signaling-mediated tumorigenesis. BILF1 homologs from primate viruses show highly conserved extracellular domains. Here, we show that conserved residues in the extracellular domains of EBV-BILF1 are important for downregulating MHC class I and that the receptor signaling and immune evasion can be inhibited by drug-like small molecules. This suggests that BILF1 could be a target to inhibit the signaling-mediated tumorigenesis and interfere with the MHC class I downregulation, thereby facilitating virus recognition by the immune system.

Epstein-Barr Virus and Systemic Autoimmune Diseases

“…As a means to avoid NK cell recognition, EBV upregulates non-classical MHC during the phase of viral protein synthesis. Lytic production of viral proteins and RNAs as well as replication of viral DNA requires that EBV can prevent cellular apoptosis and EBV has evolved an elaborate set of proteins for pacifying intracellular virus-sensing apoptosisinducing mechanisms including downregulation and inhibition of toll-like receptors (47,49,50,62,(68)(69)(70)(71).…”

Epstein-Barr Virus and Multiple Sclerosis

“…The adaptive immune response to EBV involves both Abdependent processes and cytotoxic T cells, and EBV has evolved mechanisms to evade these as described above, e.g., by downregulating MHC I to avoid recognition by cytotoxic T cells. Therefore, control of EBV relies to a large extent on natural killer cell surveillance of infected cells with too little MHC I on the surface, which is in turn counter-balanced by EBV by upregulation of non-classical MHC molecules (87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102).…”

Viral G Protein–Coupled Receptors: Attractive Targets for Herpesvirus-Associated Diseases

“…Further immunomodulatory roles for BILF1 have been proposed, including interference with CXCR4 signaling and upregulation of leukocyte adhesion molecule intercellular adhesion molecule 1 (ICAM1) expression (Nijmeijer et al, 2010;Guo et al, 2020). More widely characterized is the ability of BILF1 to downregulate cell-surface MHC class I molecule expression via a direct interaction between BILF1 and MHC molecules, leading to reduced T-cell recognition (Zuo et al, 2009(Zuo et al, , 2011Griffin et al, 2013;Fares et al, 2019). Interestingly, mutations in the N terminus and third extracellular loop of BILF1 ablated MHC class I downregulation but not constitutive GPCR signaling (Fares et al, 2019).…”

“…More widely characterized is the ability of BILF1 to downregulate cell-surface MHC class I molecule expression via a direct interaction between BILF1 and MHC molecules, leading to reduced T-cell recognition (Zuo et al, 2009(Zuo et al, , 2011Griffin et al, 2013;Fares et al, 2019). Interestingly, mutations in the N terminus and third extracellular loop of BILF1 ablated MHC class I downregulation but not constitutive GPCR signaling (Fares et al, 2019). This suggests that there are further functions of BILF1 related to signaling that are yet to be elucidated.…”