Abstract
Since the first prominent description of the orphan G protein-coupled receptor 15 (GPR15) on lymphocytes as a co-receptor for the human immunodeficiency virus (HIV) type 1 and 2 and the first report about the GPR15-triggered cytoprotective effect on vascular endothelial cells by recombinant human thrombomodulin, several decades passed before the GPR15 has been recently deorphanized. Because of new findings on GPR15, this review will summarize the consequences of GPR15 signaling considering the variety of GPR15-expressing cell types and of GPR15 ligands, with a focus on blood and vasculature.
Highlights
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In 2021, a C-terminal fragment of cystatin C but not the fulllength cystatin C was identified to bind to G protein-coupled receptor 15 (GPR15) [14] by screening a hemofiltrate (HF)derived peptide library containing peptides and small proteins circulating in human blood in their final processed and physiologically relevant forms
The findings of an increased frequency of GPR15+ lymphocytes in the blood of smokers but the absence of induction of GPR15 by smoking compounds led to the assumption that at least two factors could be responsible for GPR15 expression: one factor that triggers proliferation, and a second factor that imprints lymphocytes to express GPR15 in lymph nodes where the GPR15+ lymphocytes come from
Summary
The first activating binding partner for GPR15 was found to be exogenous particles in the form of viruses (Figures 1 and 2). With respect to endogenous binding partners, to date, there have been reports describing two different GPR15-activating ligands: one ligand of physiological origin, named C10orf, most highly expressed in the colon [13], and the other ligand of synthesized origin (recombinant human soluble thrombomodulin, ART-123) applied as an anticoagulant [8] (Figures 1 and 2). Because of its protein characteristics and features, it is proposed that this is a new type of multifunctional antimicrobial peptide It is found mainly on mucosal and skin epithelium as well as in some tumor and/or their adjacent tissues, such as esophageal cancer, hepatocellular carcinoma, squamous cell carcinoma, and invasive ductal carcinoma [15]. For C10orf activity, its extreme C-terminal residue and its hydrophobicity were considered to be necessary for optimal receptor–ligand interaction
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