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The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors

Research Project

Project/Area Number 16K19154
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Immunology
Research InstitutionOsaka University

Principal Investigator

Akiko Nakai  大阪大学, 免疫学フロンティア研究センター, 特任研究員(常勤) (80768862)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords免疫応答 / GPCR / 走化性因子受容体 / 細胞遊走 / Gタンパク共役型受容体 / 免疫学
Outline of Final Research Achievements

Lymphocyte migration is mediated by GPCRs that respond to chemoattractive molecules. After their activation, GPCRs are phosphorylated by different 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 copper metabolism MURR1 domain-containing (COMMD)8 as a protein that interacted with multiple chemoattractant receptors. COMMD8 was found to interact with COMMD3 of the same protein family (the COMMD3/8 complex). Deficiency of the COMMD8 or COMMD3 impaired B cell migration and humoral immune responses. We demonstrated that the COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of CXCR4 and activation of β-arrestin-mediated signaling. Thus, the COMMD3/8 complex functions as an adaptor that selectively recruits a specific GRK to chemoattractant receptors and represents a point of regulation for immune responses.

Academic Significance and Societal Importance of the Research Achievements

本研究において、COMMD3/8複合体がGRK6を走化性因子受容体に動員するアダプター分子として機能することが明らかになり、走化性因子受容体のシグナル伝達の新たな制御メカニズムが示された。また、B細胞特異的にCOMMD3/8複合体を欠損するマウスでは、B細胞を介した免疫応答が低下することが分かった。このことから、COMMD3/8複合体の機能を阻害することにより、過剰な免疫応答によって引き起こされる自己免疫疾患やその他の炎症性疾患の病態が改善する可能性が示された。今後、COMMD3/8複合体はこれらの疾患の治療における新たな創薬のターゲットになり得ると考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (9 results)

All 2018 2017 2016 Other

All Int'l Joint Research (4 results) Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results,  Acknowledgement Compliant: 2 results) Presentation (3 results) (of which Invited: 1 results)

  • [Int'l Joint Research] Thomas Jefferson 大学(米国)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Friedrich Schiller 大学(ドイツ)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Thomas Jefferson 大学(米国)

    • Related Report
      2016 Research-status Report
  • [Int'l Joint Research] Friedrich Schiller 大学(ドイツ)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Control of lymphocyte trafficking and adaptive immunity by adrenergic nerves2017

    • Author(s)
      Suzuki, K. and Nakai, A.
    • Journal Title

      Clin. Exp. Neuroimmunol.

      Volume: 8 Issue: 1 Pages: 15-22

    • DOI

      10.1111/cen3.12376

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Adrenergic control of the adaptive immune response by diurnal lymphocyte recirculation through lymph nodes2016

    • Author(s)
      Suzuki, K., Hayano, Y., Nakai, A., Furuta, F. and Noda, M.
    • Journal Title

      J. Exp. Med.

      Volume: 213 Issue: 12 Pages: 2567-2574

    • DOI

      10.1084/jem.20160723

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] The COMMD3/8 complex dictates the specificity of GRK recruitment to chemoattractantreceptors2018

    • Author(s)
      中井晶子
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The COMMD3/8 complex dictates the specificity of GRK recruitment to chemoattractantreceptors2018

    • Author(s)
      中井晶子
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Control of lymphocyte trafficking through b2-adrenergic receptors2017

    • Author(s)
      Akiko Nakai
    • Organizer
      RIKEN IMS Summer Program
    • Related Report
      2017 Research-status Report
    • Invited

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Published: 2016-04-21   Modified: 2022-02-21  

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