COMManDing lymphocyte migration
Keywords: Immune response, Lymphocyte migration, Chemoattractant receptor, The COMMD3/8complex, GPCR, GRK, β-arrestin

Summary of research
Lymphocyte migration is mediated by G protein-coupled receptors (GPCRs) that respond tochemoattractive molecules, represented by chemokines. Agonist binding to GPCRs activates
heteromeric G proteins to regulate the generation of second messengers that modulate downstream
signaling. Agonist-occupied GPCRs are phosphorylated by GPCR kinases (GRKs) and subsequently
recruit β-arrestins that serve as scaffolds to activate signaling molecules, including mitogen-activatedprotein kinases (MAPKs). The GRK family consists of seven mammalian members, among which
GRK2, GRK3, GRK5, and GRK6 are expressed ubiquitously. Different GRKs phosphorylate distinct
sites on the C-terminal tail of the receptor, establishing a barcode that dictates the functional
consequences of β-arrestin engagement. Thus, specific targeting of GRKs to activated GPCRs is
crucial for signal transduction. However, the molecular mechanism that determines the specificity ofGRK targeting is poorly understood. In a new study published in The Journal of Experimental Medicine,a research team led by Kazuhiro Suzuki (Professor, Immunology Frontier Research Center, OsakaUniversity) 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 migration.

In search of factors involved in GRK recruitment to chemoattractant receptors, the researchers
identified COMMD8 as a protein that binds to the C-terminal tail of a chemokine receptor CXCR4.
Additional screening revealed the interaction of COMMD8 with COMMD3. These proteins
constitutively formed a complex in the cytosol, but were translocated to the plasma membrane after
stimulation of CXCR4. The COMMD3/8 complex also interacted with other G protein-coupled
chemoattractant receptors, including CXCR5, CCR7, and the oxysterol receptor EBI2, after activationof the receptors. Interestingly, COMMD3 and COMMD8 were degraded by the proteasome in theabsence of the other, and deficiency of either protein produced the same phenotypes, indicating thatboth COMMD3 and COMMD8 are required for the stability and function of their complex. Deficiency
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of COMMD3 or COMMD8 in B cells reduced their chemotactic responses through the receptors towhich the COMMD3/8 complex was recruited. Thus, the COMMD3/8 complex is a positive regulatorof chemoattractant receptor signaling.

Mechanistic analysis for the action of the COMMD3/8 complex demonstrated that this protein complex
functions as an adaptor that selectively recruits GRK6 to chemoattractant receptors in a GRK2/3dependent manner, which promotes MAPK activation and consequently lymphocyte migration (Fig. 1).
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 type, and distinct receptor conformations
induced by ligand binding. This new study has identified a GRK-recruiting adaptor, the COMMD3/8complex, as an additional determinant of GRK specificity for GPCRs.

Consistent with the reduced chemotactic responses of COMMD3- and COMMD8-deficient B cells, themutant B cells showed multiple defects in their migration in vivo (Fig. 2A). Additionally, deficiency of
COMMD3 or COMMD8 in B cells severely impaired humoral immune responses (Fig. 2, B and C).
Therefore, the COMMD3/8 complex is essential for proper functioning of the immune system. By
exploiting the unique property of the COMMD3/8 complex, it would be possible to degrade and disable
the protein complex by pharmacological disruption of the interaction between COMMD3 and COMMD8.
Development of such drugs would provide a novel approach for immune regulation, which may be
applicable to the treatment of immune disorders.

Authors:

Akiko Nakai, Jun Fujimoto, Haruhiko Miyata, Ralf Stumm, Masashi Narazaki, StefanSchulz, Yoshihiro Baba, Atsushi Kumanogoh, Kazuhiro Suzuki*. (*corresponding)Title: “The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors.”
Journal: The Journal of Experimental Medicine (JEM online) on May 14, 2019.

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Figure 1. Proposed role of the COMMD3/8 complex in chemoattractant receptor signaling.
The COMMD3/8 complex recruits GRK6 to chemoattractant receptors through a stepwise mechanism: (i)the C-terminal tail of the activated receptor is phosphorylated by GRK2 and GRK3. (ii) the COMMD3/8complex is associated with the receptor tail through electrostatic interactions with the phosphorylated
residues. (iii) GRK6 is recruited to the receptor through the interaction with the COMMD3/8 complex andphosphorylates the C-terminal tail.

Figure 2. Deficiency of the COMMD3/8 complex impairs B cell migration and humoral immuneresponses.
(A) COMMD8-deficient (Commd8Δ) activated B cells (NP-PE+, green) show impaired migration toward theouter region of B cell follicles (IgD+ areas, red) at 3 h after immunization. (B and C) B cell-specific COMMD8deficient mice show severe defects in the antibody response (B) and generation of germinal center B cells(GL7+, red) (C). CD4 (blue) was labeled to define T cell areas in the spleen. **P < 0.01, paired t-test. Scalebars, 200 μm.
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