Evolutionary analyses reveal immune cell receptor GPR84 as a conserved receptor for bacteria-derived molecules

The G protein-coupled receptor 84 (GPR84) is found in immune cells and its expression is increased under inflammatory conditions. Activation of GPR84 by medium-chain fatty acids results in pro-inflammatory responses. Here, we screened available vertebrate genome data and found that GPR84 is present in vertebrates for more than 500 million years but absent in birds and a pseudogene in bats. Cloning and functional characterization of several mammalian GPR84 orthologs in combination with evolutionary and model-based structural analyses revealed evidence for positive selection of bear GPR84 orthologs. Naturally occurring human GPR84 variants are most frequent in Asian populations causing a loss of function. Further, we identified cis- and trans-2-decenoic acid, both known to mediate bacterial communication, as evolutionary highly conserved ligands. Our integrated set of approaches contributes to a comprehensive understanding of GPR84 in terms of evolutionary and structural aspects, highlighting GPR84 as a conserved immune cell receptor for bacteria-derived molecules.:1. ABBREVIATIONS (3) 2. INTRODUCTION (4) 2.1 Structure and signal transduction of G protein-coupled receptors (4) 2.2 The evolution of the GPCR protein superfamily (5) 2.3 GPR84, a receptor regulating immune functions (6) 2.4 Aim of the study (10) 3. PUBLICATION (11) 4. SUMMARY OF THE THESIS (37) 5. REFERENCES (40) 6. ANLAGEN (45) 6.1 Supplemental information (45) 6.2 Erklärung über die eigenständige Abfassung der Arbeit (58) 6.3 Darstellung des eigenen Beitrags (59