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GPCR kinases shape ACKR4 functions via differential C-terminal phosphorylation.

Oliver J Gerken1,2, Rebecca Warmers1,2, Clara Hild1

  • 1Institute of Cell Biology and Immunology Thurgau (BITG) at the University of Konstanz, University of Konstanz, Kreuzlingen, Switzerland.

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Atypical chemokine receptor 4 (ACKR4) binds βarrestins and regulates chemokine levels. Specific serine/threonine residues in ACKR4 control its trafficking, chemokine uptake, and interactions with GPCR kinases (GRKs).

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Last Updated: May 18, 2026

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Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Atypical chemokine receptor 4 (ACKR4) is a scavenger receptor influencing chemokine availability and G protein-coupled receptor (GPCR) signaling.
  • Unlike classical chemokine receptors, ACKR4 exclusively signals through βarrestins, lacking G protein coupling.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing ACKR4 trafficking, βarrestin recruitment, and chemokine uptake.
  • To investigate the role of ACKR4 phosphorylation by GPCR kinases (GRKs) in its function.

Main Methods:

  • Analysis of ACKR4 steady-state trafficking and endosomal cycling.
  • Identification of key serine and threonine residues in the ACKR4 tail region.
  • Investigation of ACKR4 interactions with βarrestins and GRKs.
  • Assessment of CCL19-mediated signaling and internalization.

Main Results:

  • ACKR4 constitutively associates with βarrestins and cycles between cellular compartments.
  • Specific serine/threonine clusters in the ACKR4 tail regulate trafficking, chemokine uptake, and βarrestin recruitment.
  • ACKR4 is differentially phosphorylated by GRKs (GRK5/6 and GRK2/3) in a ligand-dependent manner.
  • Apo ACKR4 forms a non-activating ternary complex with GRK2/3 and G protein.

Conclusions:

  • The ACKR4 tail region, particularly C-terminal serine/threonine clusters, is critical for βarrestin recruitment and chemokine internalization.
  • Differential GRK activity modulates ACKR4 phosphorylation and function.
  • ACKR4's unique signaling bias and phosphorylation dynamics offer insights into chemokine system regulation.