Schulze Amadeus Samuel, Kleinau Gunnar, Krakowsky Rosanna, Rochmann David, Das Ranajit, Worth Catherine L, Krumbholz Petra, Scheerer Patrick, Stäubert Claudia
Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany.
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.
iScience. 2022 Sep 6;25(10):105087. doi: 10.1016/j.isci.2022.105087. eCollection 2022 Oct 21.
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 - and -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.
G蛋白偶联受体84（GPR84）存在于免疫细胞中，在炎症条件下其表达会增加。中链脂肪酸激活GPR84会导致促炎反应。在此，我们筛选了现有的脊椎动物基因组数据，发现GPR84在脊椎动物中已存在超过5亿年，但在鸟类中不存在，在蝙蝠中为假基因。通过对几种哺乳动物GPR84直系同源物进行克隆和功能表征，并结合进化和基于模型的结构分析，发现了熊GPR84直系同源物正选择的证据。天然存在的人类GPR84变体在亚洲人群中最为常见，会导致功能丧失。此外，我们鉴定出已知介导细菌通讯的 - 和 -2-癸烯酸为进化上高度保守的配体。我们这套综合方法有助于从进化和结构方面全面了解GPR84，突出了GPR84作为细菌衍生分子的保守免疫细胞受体的地位。
