The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors

  • J Exp Med. 2019 Jul 1;216(7):1630-1647. doi: 10.1084/jem.20181494.
Akiko Nakai   #  1 ,  Jun Fujimoto   #  1  2 ,  Haruhiko Miyata  3 ,  Ralf Stumm  4 ,  Masashi Narazaki  2 ,  Stefan Schulz  4 ,  Yoshihiro Baba  5 ,  Atsushi Kumanogoh  2 ,  Kazuhiro Suzuki  6  7
Affiliations
  • 1. Laboratory of Immune Response Dynamics, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  • 2. Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 3. Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • 4. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany.
  • 5. Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 6. Laboratory of Immune Response Dynamics, Immunology Frontier Research Center, Osaka University, Osaka, Japan [email protected].
  • 7. Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • # Contributed equally.
PMID: 31088898 DOI: 10.1084/jem.20181494
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.

Products