Galectin-9 regulates dendritic cell polarity and uropod contraction by modulating RhoA activity
Adaptive immunity relies on dendritic cell (DC) migration to transport antigens from tissues to lymph nodes. Galectins, a family of β-galactoside-binding proteins, control cell membrane organization, exerting crucial roles in multiple physiological processes. Here, we report a novel mechanism underlying cell polarity and uropod retraction by demonstrating that galectin-9 regulates basal and chemokine-driven DC migration in humans and mice. Galectin-9 depletion caused a defect in RhoA signaling that resulted in impaired cell rear contractility. Mechanistically, galectin-9 interacts with and organizes CD44 at the cell surface, in turn modulating RhoA binding to GEF-H1 and the initiation of downstream signaling. Analysis of DC motility in the 3D tumor microenvironment revealed galectin-9 is also required for DC recruitment and infiltration. Exogenous galectin-9 rescued the motility of tumor-immunocompromised human blood DCs, validating the physiological relevance of galectin-9 in DC migration. Our results identify galectin-9 as a necessary mechanistic component for DC motility by regulating cell polarity and contractility, and underscore its implications for DC-based immunotherapies.
Authors
- Katarina Wolf (ORCID: https://orcid.org/0000-0003-0616-2708)
- René Classens (ORCID: https://orcid.org/0009-0004-0143-6030)
- Manon Vullings (ORCID: https://orcid.org/0000-0002-9557-0406)
- Andrea Rodgers Furones (ORCID: https://orcid.org/0000-0002-0635-4470)
- Yusuf Dölen (ORCID: https://orcid.org/0000-0001-8211-9811)
- Annemiek B. van Spriel (ORCID: https://orcid.org/0000-0002-3590-2368)
- Jorge Cuenca‐Escalona (ORCID: https://orcid.org/0000-0002-4915-1518)
- Inge M. N. Wortel (ORCID: https://orcid.org/0000-0003-3362-5229)
- Laia Querol Cano (ORCID: https://orcid.org/0000-0002-7650-9407)
- Isabel F. Stehle (ORCID: https://orcid.org/0009-0006-0957-5144)
- Stefania Di Blasio (ORCID: https://orcid.org/0000-0002-7585-8277)
- Sjoerd van Deventer (ORCID: https://orcid.org/0000-0001-8972-6665)
- Joseph H. R. Hetmanski (ORCID: https://orcid.org/0000-0002-1493-351X)
- Harry Warner (ORCID: https://orcid.org/0000-0003-2313-6974)
- Koert Schreurs
- Guus A. Franken
- Rohit Rajesh Gokhale (ORCID: https://orcid.org/0009-0007-3051-6568)
- Vince P.A. van Reijmersdal (ORCID: https://orcid.org/0009-0005-2734-8247)
- Sophie E. Klomp
Institutions
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- Brunel University of London (GB)
Publication Details
- Journal
- The Journal of Cell Biology
- Published
- 2025-09-23
- DOI
- https://doi.org/10.1083/jcb.202404079
- Citations
- 1
- Primary Topic
- Galectins and Cancer Biology
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Radboud Universitair Medisch Centrum
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute