Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 7, Pages 1630-1647Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20181494
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Funding
- Japan Society for the Promotion of Science [JP15H05656, 24790470, 23890097, JP16K19154, JP19K16690]
- Japan Science and Technology Agency (Precursory Research for Embryonic Science and Technology)
- Japan Agency for Medical Research and Development [JP18gm6210007]
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Uehara Memorial Foundation
- Naito Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [24790470, 23890097] Funding Source: KAKEN
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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 beta-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 beta-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.
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