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- Title
The dual-function chemokine receptor CCR2 drives migration and chemokine scavenging through distinct mechanisms.
- Authors
Shroka, Thomas M.; Kufareva, Irina; Salanga, Catherina L.; Handel, Tracy M.
- Abstract
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. CCR2 separates signaling from scavenging: As a G protein–coupled receptor (GPCR), CCR2 promotes monocyte migration in response to the chemokine CCL2. As a scavenger receptor for CCL2, CCR2 sequesters CCL2 intracellularly to regulate its extracellular concentration. Shroka et al. investigated whether proteins commonly involved in GPCR signaling and trafficking were required for scavenging by CCR2. The authors found that deficiencies in G proteins, the GRK family of kinases, the β-arrestin adaptor proteins, or clathrin did not affect the ability of CCR2 to scavenge. Moreover, these proteins were not involved in the constitutive internalization and recycling of CCR2 to the cell surface, processes that are critical for CCR2-mediated scavenging. These results raise the possibility that the signaling and scavenging populations of CCR2 could be pharmacologically targeted independently.—WW
- Subjects
CHEMOKINE receptors; G protein coupled receptors; CLATHRIN; ADAPTOR proteins; G proteins; TRAFFIC signs &; signals
- Publication
Science Signaling, 2023, Vol 16, Issue 770, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abo4314