IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-65858-x.html
   My bibliography  Save this article

Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies

Author

Listed:
  • Claudia V. Perez Almeria

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Omolade Otun

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science
    INSERM, Institut de Génomique Fonctionnelle (IGF), University of Montpellier, CNRS)

  • Roman Schlimgen

    (Medical College of Wisconsin, Department of Biochemistry)

  • Thomas D. Lamme

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Lotte Di Niro

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Caitrin Crudden

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Jan Paul Bebelman

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Noureldine Youssef

    (Friedrich-Schiller-University Jena, Institute for Molecular Cell Biology, CMB – Center for Molecular Biomedicine, University Hospital Jena)

  • Lejla Musli

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Shawn Jenjak

    (Medical College of Wisconsin, Department of Biochemistry)

  • Vladimir Bobkov

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Julia Drube

    (Friedrich-Schiller-University Jena, Institute for Molecular Cell Biology, CMB – Center for Molecular Biomedicine, University Hospital Jena)

  • Carsten Hoffmann

    (Friedrich-Schiller-University Jena, Institute for Molecular Cell Biology, CMB – Center for Molecular Biomedicine, University Hospital Jena)

  • Brian F. Volkman

    (Medical College of Wisconsin, Department of Biochemistry)

  • Sébastien Granier

    (INSERM, Institut de Génomique Fonctionnelle (IGF), University of Montpellier, CNRS)

  • Cherine Bechara

    (INSERM, Institut de Génomique Fonctionnelle (IGF), University of Montpellier, CNRS
    Institut Universitaire de France)

  • Marco Siderius

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Raimond Heukers

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science
    QVQ Holding BV)

  • Christopher T. Schafer

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

  • Martine J. Smit

    (Vrije Universiteit, Amsterdam Institute for Molecular and Life Sciences (AIMMS), Department of Chemistry & Pharmaceutical Sciences, Division of Medicinal Chemistry, Faculty of Science)

Abstract

Stimulation of atypical chemokine receptor 3 (ACKR3) by chemokines does not activate G proteins but recruits arrestin. It is a chemokine scavenger that indirectly influences responses by restricting the availability of CXCL12, an agonist shared with the canonical receptor CXCR4. ACKR3 is upregulated in numerous disorders. Due to limited insights in chemokine-activated ACKR3 signaling, it is unclear how ACKR3 contributes to pathological phenotypes. One explanation may be that constitutive activity of ACKR3 drives non-canonical signaling through a basal receptor state. Here we characterize the constitutive responses of ACKR3 using inverse agonistic nanobodies to suppress its basal activity. These tools promote an inactive receptor conformation which decreased arrestin engagement and inhibited constitutive internalization. Basal non-chemotactic, cancer cell motility was also suppressed, suggesting a role for ACKR3 in this process. The basal receptor activity in pathophysiology may provide an alternate therapeutic approach for targeting ACKR3.

Suggested Citation

  • Claudia V. Perez Almeria & Omolade Otun & Roman Schlimgen & Thomas D. Lamme & Lotte Di Niro & Caitrin Crudden & Jan Paul Bebelman & Noureldine Youssef & Lejla Musli & Shawn Jenjak & Vladimir Bobkov & , 2025. "Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65858-x
    DOI: 10.1038/s41467-025-65858-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-65858-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-65858-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65858-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.