Evolutionary analyses reveal immune cell receptor GPR84 as a conserved receptor for bacteria-derived molecules
Amadeus Samuel Schulze,
Gunnar Kleinau,
Rosanna Krakowsky,
David Rochmann,
Ranajit Das,
Catherine L. Worth,
Petra Krumbholz,
Patrick Scheerer,
Claudia Stäubert
Affiliations
Amadeus Samuel Schulze
Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany
Gunnar Kleinau
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, 10117 Berlin, Germany
Rosanna Krakowsky
Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany
David Rochmann
Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany
Ranajit Das
Yenepoya Research Centre, Yenepoya University, Mangalore, Karnataka, India
Catherine L. Worth
Independent Data Lab UG, Frauenmantelanger 31, 80937 Munich, Germany
Petra Krumbholz
Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany
Patrick Scheerer
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Physics and Biophysics, Group Protein X-ray Crystallography and Signal Transduction, Charitéplatz 1, 10117 Berlin, Germany
Claudia Stäubert
Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany; Corresponding author
Summary: 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.
