Receptor Determinants for b- Arrestin Functional Specificity at C-X-C Chemokine Receptor 5

被引：0
作者：
Crecelius, Joseph M. [1 ]
Manz, Aaren R. [1 ]
Benzow, Sara [1 ]
Marchese, Adriano [1 ]
机构：
[1] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI USA
来源：
MOLECULAR PHARMACOLOGY | 2024年 / 106卷 / 06期
基金：
美国国家卫生研究院;
关键词：
PROTEIN-COUPLED RECEPTOR; BETA-ARRESTIN; ADAPTER MOLECULE-1; CLATHRIN ADAPTER; TERMINAL TAIL; IDENTIFICATION; TRAFFICKING; RECRUITMENT; KINASES; CXCR4;
D O I：
10.1124/molpharm.124.000942
中图分类号：
R9 [药学];
学科分类号：
1007 ;
摘要：
/3-arrestins are multifaceted adaptor proteins that mediate G protein-coupled receptor (GPCR) desensitization, internalization, and signaling. It is emerging that receptor-specific determinants specify these divergent functions at GPCRs, yet this remains poorly understood. Here, we set out to identify the receptor determinants responsible for /3-arrestin-mediated regulation of the chemokine receptor C-X-C motif chemokine receptor 5 (CXCR5). Using bioluminescence resonance energy transfer, we show that /3-arrestin1 and /3-arrestin2 are dose- dependently recruited to CXCR5 by its cognate ligand C-X-C motif chemokine ligand 13 (CXCL13). The carboxy-terminal tail of CXCR5 contains several serine/threonine residues that can be divided into three discrete phospho-site clusters based on their position relative to transmembrane domain 7. Mutagenesis experiments revealed that the distal and medial phospho-site clusters, but not the proximal, are required for agonist-stimulated /3-arrestin1 or /3-arrestin2 recruitment to CXCR5. Consistent with this, we provide evidence that the distal and medial, but not proximal, phospho-site clusters are required for receptor desensitization. Surprisingly, the individual phospho-site clusters are not required for agonist-stimulated internalization of CXCR5. Further, we show that CXCL13-stimulated CXCR5 internalization and ERK1/2 phosphorylation, but not desensitization, remain intact in human embryonic kidney 293 cells lacking /3-arrestin1 and /3-arrestin2. Our study provides evidence that /3-arrestins are recruited to CXCR5 and are required for desensitization but are dispensable for internalization or signaling, suggesting that discrete receptor determinants specify the divergent functions of /3-arrestins. SIGNIFICANCE STATEMENT C-X-C motif ligand 13 (CXCL13) and C-X-C motif chemokine receptor 5 (CXCR5) are important in the immune system and are linked to diseases, yet regulation of CXCR5 signaling remains poorly understood. We provide evidence that a phospho-site cluster located at the extreme distal carboxyl-terminal tail of the receptor is responsible for /3-arrestin recruitment and receptor desensitization. /3-arrestins are not required for CXCL13stimulated internalization or signaling, indicating that /3-arrestins perform only one of their functions at CXCR5 and that discrete receptor determinants specify the divergent functions of /3-arrestins.
引用
收藏
页码：287 / 297
页数：11
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