Teplatz 1, 10117 Berlin, Germany3Yenepoya2Charite Analysis Centre, Yenepoya University, Mangalore, Karnataka, India Information Lab UG, Frauenmantelanger 31, 80937 Munich, Germany authors contributed equally4Independent5These6LeadcontactCorrespondence: claudia.staeubert@medizin. uni-leipzig.de doi.org/10.1016/j.isci. 2022.iScience 25, 105087, October 21, 2022 2022 The Author(s). That is an open access short article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).OPEN ACCESSlliScienceArticleIn the present study, we hypothesized that GPR84 orthologs from diverse mammalian species exhibit variations in sequence and signaling properties because of species- or order-specific adaptations to variables like habitat or way of life, like eating plan and linked microbial challenges for the immune program. To address this hypothesis, GPR84 sequences of more than 200 vertebrate species (ortholog identification) were collected from public databases and analyzed for conservation/variation, loss of selective constraints, or signatures of constructive choice.EGF Protein Purity & Documentation Many mammalian GPR84 orthologs had been cloned and functionally compared. The chosen mammalian species colonize diverse habitats and hence are faced with a variety of environmental conditions, but also differ in size and dietary specifications. While a number of potent surrogate GPR84 ligands have been described (Mahmud et al., 2017; Pillaiyar et al., 2017, 2018; Kose et al., 2020), we stimulated the mammalian GPR84 orthologs together with the naturally occurring MCFA decanoic acid (C10) and also the 3-OH-MCFA 3-hydroxydecanoic acid (3-OH-C10). Both, C10 and 3-OHC-10 are assumed to be orthosteric endogenous ligands, and hence their binding web sites are far more most likely subjected to purifying evolutionary choice, whereas allosteric websites are often additional divergent (reviewed in (Wenthur et al., 2014)). Additionally, naturally occurring human GPR84 variants, i.e. heterozygous single nucleotide polymorphisms (SNPs) and somatic mutations, had been functionally analyzed with regards to their influence on GPR84 signaling. These studies had been accompanied by GPR84 homology models to extrapolate hot spots of receptor variations within the 3D structure, and thereby associate sequence information and facts with functional data at a structural level. Finally, we tested so far unknown potential GPR84 ligands, thinking of the function of this receptor as an immune cell receptor. We discovered the bacterial quorum sensing molecules cis-2-decenoic acid (cis-2-C10) and trans-2-decenoic acid (trans-2-C10) as potent agonists of mammalian GPR84 orthologs. Our combined set of approaches yields insights into the evolutionary history of GPR84 as a conserved receptor for microbiota-derived metabolites with relevance for immune function.RESULTSIt has previously been shown that GPR84 is present in zebrafish and mediates, as in humans, pro-inflammatory signaling on activation, reflected in enhanced phagocytosis in macrophages (Huang et al.Streptavidin Magnetic Beads Publications , 2014; Recio et al.PMID:24914310 , 2018; Lucy et al., 2019; Wang et al., 2019). As a result, as a result of its functionality in teleost fish, GPR84 occurrence has been dated back at least 400 Myr (Renshaw and Trede, 2012). Here, we mined publicly available nucleotide databases to gather vertebrate GPR84 ortholog data (NCBI accession numbers in Table S1), which we analyzed for changing evolutionary constraints and sequence conservation. To our very best information, no study has so far systematically and functionally addressed elements of GPR84 vertebrate evolution.GPR84 i.
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