The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors

Akiko Nakai, Jun Fujimoto, Haruhiko Miyata, Ralf Stumm, Masashi Narazaki, Stefan Schulz, Yoshihiro Baba, Atsushi Kumanogoh, Kazuhiro Suzuki

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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 b-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 b-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.

Original languageEnglish
Pages (from-to)1630-1647
Number of pages18
JournalJournal of Experimental Medicine
Volume216
Issue number7
DOIs
Publication statusPublished - Jan 1 2019

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Nakai, A., Fujimoto, J., Miyata, H., Stumm, R., Narazaki, M., Schulz, S., ... Suzuki, K. (2019). The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors. Journal of Experimental Medicine, 216(7), 1630-1647. https://doi.org/10.1084/jem.20181494