Abstract
Endocytosis is a fundamental process involved in trafficking of various extracellular and transmembrane molecules from the cell surface to its interior. This enables cells to communicate and respond to external environments, maintain cellular homeostasis, and transduce signals. G protein-coupled receptors (GPCRs) constitute a family of receptors with seven transmembrane alpha-helical domains (7TM receptors) expressed at the cell surface, where they regulate physiological and pathological cellular processes. Several herpesviruses encode receptors (vGPCRs) which benefits the virus by avoiding host immune surveillance, supporting viral dissemination, and thereby establishing widespread and lifelong infection, processes where receptor signaling and/or endocytosis seem central. vGPCRs are rising as potential drug targets as exemplified by the cytomegalovirus-encoded receptor US28, where its constitutive internalization has been exploited for selective drug delivery in virus infected cells. Therefore, studying GPCR trafficking is of great importance. This review provides an overview of the current knowledge of endocytic and cell localization properties of vGPCRs and methodological approaches used for studying receptor internalization. Using such novel approaches, we show constitutive internalization of the BILF1 receptor from human and porcine γ-1 herpesviruses and present motifs from the eukaryotic linear motif (ELM) resources with importance for vGPCR endocytosis.
Highlights
The most common endocytic pathways employed by G protein-coupled receptors (GPCRs) to enter the cell are reviewed, alongside the novel approaches used to study GPCR mediated endocytosis and endocytic properties of most commonly studied vGPCRs: US28, ORF74, and BILF1
This review has focused on three thoroughly studied vGPCRs (HCMV-US28, Kaposi’s Sarcoma Associated Herpesvirus (KSHV)-ORF74, and Epstein barr virus (EBV)-BILF1 and homologs of these) in terms of endocytic properties as well as novel methods used for characterization of endocytic properties
Despite their distant genetic relationships, US28, ORF74, and BILF1 receptors have been linked to the development of cancer
Summary
Endocytosis encompasses different routes by which a cell uptakes extracellular material from the surface and transports it into the cell thereby maintaining homeostasis between the extracellular and intracellular environment [1]. It is believed that during evolutionary processes, viruses took over genes for these receptors from their hosts and rearranged them to function in the benefit of the virus [10,11,12] They imitate the function of endogenous human receptors and use them to subvert cellular signaling, avoid cell immune responses, induce cell transformation, and support viral dissemination and replication [12,13]. BILF1 receptors, encoded by gamma-1 herpesviruses, have recently been recognized as the first immune evasive vGPCR able to downregulate surface MHC class I molecules at the cell surface [15]. Initial localization of these receptors in the cell, and additional trafficking, are important processes that control the signaling capacity of these receptors. The most common endocytic pathways employed by GPCRs to enter the cell are reviewed, alongside the novel approaches used to study GPCR mediated endocytosis and endocytic properties of most commonly studied vGPCRs: US28, ORF74, and BILF1
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