Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
Walloon Excellence in Life Sciences and Biotechnology (Welbio), 1300 Wavre, Belgium.
Cells. 2022 Mar 18;11(6):1037. doi: 10.3390/cells11061037.
Atypical chemokine receptors (ACKRs) have emerged as a subfamily of chemokine receptors regulating the local bioavailability of their ligands through scavenging, concentration, or transport. The biological roles of ACKRs in human physiology and diseases are often studied by using transgenic mouse models. However, it is unknown whether mouse and human ACKRs share the same properties. In this study, we compared the properties of the human and mouse atypical chemerin receptor GPR1 and showed that they behave differently regarding their interaction with β-arrestins. Human hGPR1 interacts with β-arrestins as a result of chemerin stimulation, whereas its mouse orthologue mGPR1 displays a strong constitutive interaction with β-arrestins in basal conditions. The constitutive interaction of mGPR1 with β-arrestins is accompanied by a redistribution of the receptor from the plasma membrane to early and recycling endosomes. In addition, β-arrestins appear mandatory for the chemerin-induced internalization of mGPR1, whereas they are dispensable for the trafficking of hGPR1. However, mGPR1 scavenges chemerin and activates MAP kinases ERK1/2 similarly to hGPR1. Finally, we showed that the constitutive interaction of mGPR1 with β-arrestins required different structural constituents, including the receptor C-terminus and arginine 3.50 in the second intracellular loop. Altogether, our results show that sequence variations within cytosolic regions of GPR1 orthologues influence their ability to interact with β-arrestins, with important consequences on GPR1 subcellular distribution and trafficking.
非典型趋化因子受体（ACKR）作为趋化因子受体的一个亚家族出现，通过清除、浓缩或转运来调节其配体的局部生物利用度。ACKR 在人体生理和疾病中的生物学作用通常通过使用转基因小鼠模型来研究。然而，尚不清楚小鼠和人类 ACKR 是否具有相同的特性。在这项研究中，我们比较了人类和小鼠非典型趋化因子受体 GPR1 的特性，并表明它们在与β-arrestin 的相互作用方面表现出不同的特性。人 hGPR1 与β-arrestin 的相互作用是由于 chemerin 的刺激，而其小鼠同源物 mGPR1 在基础条件下与β-arrestin 表现出强烈的组成性相互作用。mGPR1 与β-arrestin 的组成性相互作用伴随着受体从质膜重新分布到早期和再循环内体。此外，β-arrestin 似乎是 chemerin 诱导 mGPR1 内化所必需的，而对于 hGPR1 的转运则是可有可无的。然而，mGPR1 可以清除 chemerin 并激活 MAP 激酶 ERK1/2，与 hGPR1 相似。最后，我们表明 mGPR1 与β-arrestin 的组成性相互作用需要不同的结构成分，包括受体的 C 末端和第二细胞内环中的精氨酸 3.50。总之，我们的结果表明，GPR1 同源物细胞溶质区域内的序列变异会影响它们与β-arrestin 的相互作用能力，这对 GPR1 的亚细胞分布和转运有重要影响。
