Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies
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.
Authors
- Caitrin Crudden (ORCID: https://orcid.org/0000-0002-7786-112X)
- Carsten Hoffmann (ORCID: https://orcid.org/0000-0003-0884-9300)
- Marco Siderius (ORCID: https://orcid.org/0000-0003-3630-4228)
- Christopher T. Schafer (ORCID: https://orcid.org/0000-0001-9907-295X)
- Martine J. Smit (ORCID: https://orcid.org/0000-0003-2713-0238)
- Vladimir Bobkov (ORCID: https://orcid.org/0000-0002-5414-8188)
- Roman R. Schlimgen (ORCID: https://orcid.org/0000-0003-3395-5519)
- Jan Paul Bebelman (ORCID: https://orcid.org/0000-0002-6264-2004)
- Claudia V. Perez Almeria (ORCID: https://orcid.org/0000-0002-7312-8529)
- Sébastien Granier (ORCID: https://orcid.org/0000-0003-1550-3658)
- Chérine Bechara (ORCID: https://orcid.org/0000-0002-5539-6327)
- Raimond Heukers (ORCID: https://orcid.org/0000-0003-4498-7751)
- Omolade Otun (ORCID: https://orcid.org/0009-0008-7319-0200)
- Noureldine Youssef (ORCID: https://orcid.org/0000-0001-8958-1646)
- Shawn Jenjak (ORCID: https://orcid.org/0000-0002-2142-334X)
- Julia Drube (ORCID: https://orcid.org/0000-0001-6188-2279)
- Brian F. Volkman (ORCID: https://orcid.org/0000-0002-6681-5179)
- Lotte Di Niro (ORCID: https://orcid.org/0009-0008-9553-0667)
- Thomas D Lamme (ORCID: https://orcid.org/0009-0005-2168-9809)
- Lejla Musli
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Universitaire de France (FR)
- Université de Montpellier (FR)
- Medical College of Wisconsin (US)
- Qserve Group (Netherlands) (NL)
- Jena University Hospital (DE)
- Institut de Génomique Fonctionnelle (FR)
- Friedrich Schiller University Jena (DE)
- Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1038/s41467-025-65858-x
- Citations
- 1
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- European Commission
- Agence Nationale de la Recherche
- ZonMw
- Région Occitanie Pyrénées-Méditerranée
- Laboratoire d'Excellence EpiGenMed
- National Institutes of Health
- Horizon 2020 Framework Programme
- National Institute of Allergy and Infectious Diseases