PT  - JOURNAL ARTICLE
AU  - Christopher T. Schafer
AU  - Qiuyan Chen
AU  - John J. G. Tesmer
AU  - Tracy M. Handel
TI  - Atypical Chemokine Receptor 3 ‘Senses’ CXC Chemokine Receptor 4 Activation Through GPCR Kinase Phosphorylation
AID  - 10.1101/2023.02.25.530029
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.02.25.530029
4099  - http://biorxiv.org/content/early/2023/03/10/2023.02.25.530029.short
4100  - http://biorxiv.org/content/early/2023/03/10/2023.02.25.530029.full
AB  - Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging action mediates the availability of the chemokine CXCL12 for the G protein-coupled receptor (GPCR) CXCR4 and requires phosphorylation of the ACKR3 C-terminus by GPCR kinases (GRKs). ACKR3 is phosphorylated by GRK2 and GRK5, but the mechanisms by which these kinases regulate the receptor are unresolved. Here we mapped the phosphorylation patterns and determined that GRK5 phosphorylation of ACKR3 dominates β-arrestin recruitment and chemokine scavenging over GRK2. Co-activation of CXCR4 significantly enhanced phosphorylation by GRK2 through the liberation of Gβγ. These results suggest that ACKR3 ‘senses’ CXCR4 activation through a GRK2-dependent crosstalk mechanism. Surprisingly, we also found that despite the requirement for phosphorylation, and the fact that most ligands promote β-arrestin recruitment, β-arrestins are dispensable for ACKR3 internalization and scavenging, suggesting a yet to be determined function for these adapter proteins.Competing Interest StatementT.M.H. is a cofounder of Lassogen Inc. and serves on the Scientific Advisory Boards of Artica, Abilita Bio, and Abalone Bio. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. The other authors declare that they have no competing interests.