ACKR3 Regulation of Neuronal Migration Requires ACKR3 Phosphorylation, but Not β-Arrestin.

作者：Friederike Saaber, D. Schütz, E. Miess, Philipp Abe, Srinidhi Desikan, Praveen Ashok Kumar, S. Balk, Keting Huang, J. Beaulieu, S. Schulz, R. Stumm · 发表于：Cell Reports · 年份：2019 · DOI：10.1016/j.celrep.2019.01.049 · 被引用次数：69 · 研究领域：Medicine、Chemistry

Phosphorylation of heptahelical receptors is thought to regulate G protein signaling, receptor endocytosis, and non-canonical signaling via recruitment of β-arrestins. We investigated chemokine receptor functionality under phosphorylation-deficient and β-arrestin-deficient conditions by studying interneuron migration in the embryonic cortex. This process depends on CXCL12, CXCR4, G protein signaling and on the atypical CXCL12 receptor ACKR3. We found that phosphorylation was crucial, whereas β-arrestins were dispensable for ACKR3-mediated control of CXCL12 levels in vivo. Cortices of mice expressing phosphorylation-deficient ACKR3 exhibited a major interneuron migration defect, which was accompanied by excessive activation and loss of CXCR4. Cxcl12-overexpressing mice mimicked this phenotype. Excess CXCL12 caused lysosomal CXCR4 degradation, loss of CXCR4 responsiveness, and, ultimately, similar motility defects as Cxcl12 deficiency. By contrast, β-arrestin deficiency caused only a subtle migration defect mimicked by CXCR4 gain of function. These findings demonstrate that phosphorylation regulates atypical chemokine receptor function without β-arrestin involvement in chemokine sequestration and non-canonical signaling.