TY - JOUR
T1 - The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors
AU - Nakai, Akiko
AU - Fujimoto, Jun
AU - Miyata, Haruhiko
AU - Stumm, Ralf
AU - Narazaki, Masashi
AU - Schulz, Stefan
AU - Baba, Yoshihiro
AU - Kumanogoh, Atsushi
AU - Suzuki, Kazuhiro
N1 - Funding Information:
This work was supported by grants from the Japan Society for the Promotion of Science to K. Suzuki (JP15H05656, 24790470, and 23890097) and A. Nakai (JP16K19154 and JP19K16690), the Japan Science and Technology Agency (Precursory Research for Embryonic Science and Technology), the Japan Agency for Medical Research and Development (JP18gm6210007), the Mo-chida Memorial Foundation for Medical and Pharmaceutical Research, the Uehara Memorial Foundation, the Naito Foundation, and the Takeda Science Foundation to K. Suzuki. The authors declare no competing financial interests.
Publisher Copyright:
© 2019 Nakai et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20181494
DO - 10.1084/jem.20181494
M3 - Article
C2 - 31088898
AN - SCOPUS:85069266701
VL - 216
SP - 1630
EP - 1647
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 7
ER -