Abstract
Lymphocyte migration is mediated by G protein-coupled receptors (GPCRs) that respond to chemoattractive molecules. After their activation, GPCRs are phosphorylated by different GPCR kinases (GRKs), which produces distinct functional outcomes through β-arrestins. However, the molecular machinery that targets individual GRKs to activated GPCRs remains elusive. Here, we identified a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex) as an adaptor that selectively recruits a specific GRK to chemoattractant receptors and promotes lymphocyte chemotaxis. COMMD8, whose stability depended on COMMD3, was recruited to multiple chemoattractant receptors. Deficiency of COMMD8 or COMMD3 impaired B cell migration and humoral immune responses. Using CXC-chemokine receptor 4 (CXCR4) as a model, we demonstrated that the COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of the receptor and activation of β-arrestin-mediated signaling. Thus, the COMMD3/8 complex is a specificity determinant of GRK targeting to GPCRs and represents a point of regulation for immune responses.
Highlights
G protein–coupled receptors (GPCRs) comprise the largest family of surface receptors and regulate a broad spectrum of biological processes (Lefkowitz, 2007)
The COMMD3/8 complex interacts with chemoattractant receptors In search of factors involved in GPCR kinases (GRKs) recruitment to chemoattractant receptors, we performed yeast two-hybrid screening of a cDNA library from human bone marrow and identified COMMD8 as a protein that binds to the C-terminal amino acid sequence of human CXC-chemokine receptor 4 (CXCR4)
It has been suggested that the specificity of GRK recruitment to GPCRs is determined by the relative expression levels of individual GRKs, which vary among cell types (Violin et al, 2006; Tobin et al, 2008), and distinct receptor conformations induced by ligand binding (Nobles et al, 2011)
Summary
G protein–coupled receptors (GPCRs) comprise the largest family of surface receptors and regulate a broad spectrum of biological processes (Lefkowitz, 2007). Once lymphocytes encounter cognate antigens, they rapidly change their migration program to efficiently induce immune responses in the lymphoid organ. Each of these steps of lymphocyte trafficking is controlled by a specific chemoattractant receptor(s). CXCR5 is essential for B cell localization in lymphoid follicles (Forster et al, 1996; Ansel et al, 2000), which is a prerequisite for antigen encounter of the cells (Junt et al, 2005; Suzuki et al, 2009). B cells up-regulate the expression of the oxysterol receptor Epstein-Barr virus–induced gene 2 (EBI2; known as GPR183; Gatto et al, 2009; Pereira et al, 2009) and CCR7 (Reif et al, 2002; Okada and Cyster, 2006), which directs their positioning to facilitate further acquisition of the antigen and encounters with cognate T cells and thereby promotes humoral immune responses
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