2. Academic Validation
  3. The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors

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

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 ksuzuki@ifrec.osaka-u.ac.jp.
  • 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.

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