LRBA regulates actin cytoskeleton dynamics through NMIIA during B cell immune responses
Patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency typically suffer from severe B cell dysfunction. However, the underlying mechanisms remain incompletely understood. In this study, we identify non-muscle myosin IIA (NMIIA) as an interaction partner of LRBA in B cells, and uncover a role for LRBA in regulating actin cytoskeleton dynamics during B cell activation. LRBA-deficient B cells exhibit abnormal migration, impaired F-actin polymerization, and reduced B cell receptor signalling and polarization upon activation. In addition, LRBA deficiency severely disrupts immune synapse formation as evidenced by diminished central SMAC formation, reduced microtubule organizing center translocation and disrupted BCR and lysosome polarization. Consistent with these defects, internalization of the BCR-antigen complex is also impaired. Mechanistically, NMIIA activation, assessed by myosin light chain (MLC) phosphorylation, is reduced in LRBA-deficient cells. In addition, LRBA co-localizes with active NMIIA during both migration and immune synapse formation. Collectively, our findings establish LRBA as an important regulator of cytoskeleton dynamics during B cell activation, which may contribute to the defective humoral immunity observed in LRBA-deficient patients.
Authors
- Hannah van Dijk (ORCID: https://orcid.org/0000-0002-9712-8371)
- Emily Margaret Mace (ORCID: https://orcid.org/0000-0003-0226-7393)
- Tatjana I. Cornu (ORCID: https://orcid.org/0000-0002-7206-7541)
- Juan Eduardo Montero-Hernández (ORCID: https://orcid.org/0000-0003-1158-6978)
- Virginia Andreani (ORCID: https://orcid.org/0000-0002-8991-038X)
- Laura Gámez‐Díaz (ORCID: https://orcid.org/0000-0002-6800-9736)
- Yolanda R. Carrasco (ORCID: https://orcid.org/0000-0003-2148-1926)
- Volker Spindler (ORCID: https://orcid.org/0000-0002-1302-5421)
- Jörn Dengjel (ORCID: https://orcid.org/0000-0002-9453-4614)
- Frédéric Gros (ORCID: https://orcid.org/0000-0002-6252-4323)
- Fernando E. Sepulveda (ORCID: https://orcid.org/0000-0001-5865-4929)
- Kerstin Geiger (ORCID: https://orcid.org/0009-0000-8107-640X)
- Bodo Grimbacher (ORCID: https://orcid.org/0000-0002-6897-6806)
- Quentin Frenger (ORCID: https://orcid.org/0000-0002-2057-3813)
- Manuel Rhiel (ORCID: https://orcid.org/0000-0003-0741-2780)
- Elena Sindram (ORCID: https://orcid.org/0000-0002-5700-7364)
- Anna Lang
- Rebecca Marsiske (ORCID: https://orcid.org/0009-0006-5870-5080)
- Vanessa Zeidler (ORCID: https://orcid.org/0009-0004-6548-5712)
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Fribourg (CH)
- Inserm (FR)
- Universität Hamburg (DE)
- University of Freiburg (DE)
- University of Basel (CH)
- Université Paris Cité (FR)
- University Medical Center Freiburg (DE)
- Institut Necker Enfants Malades (FR)
- Centre National pour la Recherche Scientifique et Technique (CNRST) (MA)
- Centro Nacional de Biotecnología (ES)
- University Medical Center Hamburg-Eppendorf (DE)
- German Center for Infection Research (DE)
- Laboratoire d'études sur les monothéismes (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Université de Strasbourg (FR)
- Columbia University (US)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-06-12
- DOI
- https://doi.org/10.1038/s44319-026-00831-3
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wilhelm Sander-Stiftung
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Bundesministerium für Bildung und Forschung
- Albert-Ludwigs-Universität Freiburg
- European Society for Immunodeficiencies
- Agencia Estatal de Investigación
- Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
- Centro Nacional de Biotecnología