Biomedical Sciences Program, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Sci Signal. 2023 Jan 31;16(770):eabo4314. doi: 10.1126/scisignal.abo4314.
C-C chemokine receptor 2 (CCR2) is a dual-function receptor. Similar to other G protein-coupled chemokine receptors, it promotes monocyte infiltration into tissues in response to the chemokine CCL2, and, like atypical chemokine receptors (ACKRs), it scavenges chemokine from the extracellular environment. CCR2 therefore mediates CCL2-dependent signaling as a G protein-coupled receptor (GPCR) and also limits CCL2 signaling as a scavenger receptor. We investigated the mechanisms underlying CCR2 scavenging, including the involvement of intracellular proteins typically associated with GPCR signaling and internalization. Using CRISPR knockout cell lines, we showed that CCR2 scavenged by constitutively internalizing to remove CCL2 from the extracellular space and recycling back to the cell surface for further rounds of ligand sequestration. This process occurred independently of G proteins, GPCR kinases (GRKs), β-arrestins, and clathrin, which is distinct from other "professional" chemokine scavenger receptors that couple to GRKs, β-arrestins, or both. These findings set the stage for understanding the molecular regulators that determine CCR2 scavenging and may have implications for drug development targeting this therapeutically important receptor.
C-C 趋化因子受体 2（CCR2）是一种双功能受体。与其他 G 蛋白偶联趋化因子受体类似，它促进单核细胞浸润到组织中，以响应趋化因子 CCL2，并且与非典型趋化因子受体（ACKR）一样，它从细胞外环境中清除趋化因子。因此，CCR2 通过作为 G 蛋白偶联受体（GPCR）介导 CCL2 依赖性信号转导，并且还作为清除受体限制 CCL2 信号转导。我们研究了 CCR2 清除的机制，包括与 GPCR 信号转导和内化相关的细胞内蛋白的参与。使用 CRISPR 敲除细胞系，我们表明 CCR2 通过组成型内化来清除细胞外空间中的 CCL2，并回收回细胞表面以进行进一步的配体隔离，从而清除 CCL2。这个过程独立于 G 蛋白、GPCR 激酶（GRKs）、β-arrestin 和网格蛋白，这与其他与 GRKs、β-arrestin 或两者结合的“专业”趋化因子清除受体不同。这些发现为理解决定 CCR2 清除的分子调节剂奠定了基础，并可能对靶向该治疗上重要受体的药物开发具有意义。
