2. Academic Validation
  3. Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients

Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients

  • Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2119483119. doi: 10.1073/pnas.2119483119.
Eva M García-Cuesta 1,  José Miguel Rodríguez-Frade 1,  Sofía R Gardeta 1 2,  Gianluca D'Agostino 1,  Pablo Martínez 1,  Blanca Soler Palacios 1,  Graciela Cascio 3,  Tobias Wolf 4,  Nicolas Mateos 5,  Rosa Ayala-Bueno 1,  César A Santiago 6,  Pilar Lucas 1,  Lucia Llorente 7,  Luis M Allende 7,  Luis Ignacio González-Granado 7 8,  Noa Martín-Cófreces 9 10 11,  Pedro Roda-Navarro 7 12,  Federica Sallusto 4 13,  Francisco Sánchez-Madrid 9 10 11,  María F García-Parajo 5 14,  Laura Martínez-Muñoz 15 16,  Mario Mellado 1
Affiliations

Affiliations

  • 1 Chemokine Signaling Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, E-28049 Madrid, Spain.
  • 2 Department of Molecular Biosciences, Universidad Autónoma de Madrid, E-28049 Madrid, Spain.
  • 3 Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
  • 4 Institute of Microbiology, ETH Zürich, 8092 Zürich, Switzerland.
  • 5 Institut de Ciencies Fotoniques, Barcelona Institute of Science and Technology, E-08860 Barcelona, Spain.
  • 6 X-ray Crystallography Unit, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, E-28049 Madrid, Spain.
  • 7 12 de Octubre Health Research Institute (imas12), E-28012 Madrid, Spain.
  • 8 Department of Public Health School of Medicine, School of Medicine Universidad Complutense de Madrid, E-28040 Madrid, Spain.
  • 9 Immunology Service, Hospital Universitario de la Princesa, UAM, IIS-IP, E-28006 Madrid, Spain.
  • 10 Area of Vascular Pathophysiology, Laboratory of Intercellular Communication, Fundación Centro Nacional de Investigaciones Cardiovasculares-Carlos III, E-28029 Madrid, Spain.
  • 11 Centro de Investigación Básica en Red cardiovascular, E-28029 Madrid, Spain.
  • 12 Department of Immunology, Ophthalmology, and ENT, School of Medicine, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
  • 13 Institute for Research in Biomedicine, Bellinzona, Università della Svizzera Italiana, 6900 Lugano, Switzerland.
  • 14 Institutió Catalana de Recerca i Estudis Avançats, E-08010 Barcelona, Spain.
  • 15 Department of Cell Signaling, Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Cientificas, E-41092 Seville, Spain.
  • 16 Department of Medical Biochemistry, Molecular Biology, and Immunology, University of Seville, Medical School, E-41004 Seville, Spain.
PMID: 35588454 DOI: 10.1073/pnas.2119483119
Abstract

Chemokine Receptor nanoscale organization at the cell membrane is orchestrated by the actin Cytoskeleton and influences cell responses. Using single-particle tracking analysis we show that CXCR4R334X, a truncated mutant Chemokine Receptor linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis), fails to nanoclusterize after CXCL12 stimulation, and alters the lateral mobility and spatial organization of CXCR4 when coexpressed. These findings correlate with multiple phalloidin-positive protrusions in cells expressing CXCR4R334X, and their inability to correctly sense chemokine gradients. The underlying mechanisms involve inappropriate actin Cytoskeleton remodeling due to the inadequate β-arrestin1 activation by CXCR4R334X, which disrupts the equilibrium between activated and deactivated cofilin. Overall, we provide insights into the molecular mechanisms governing CXCR4 nanoclustering, signaling and cell function, and highlight the essential scaffold role of β-arrestin1 to support CXCL12-mediated actin reorganization and receptor clustering. These defects associated with CXCR4R334X expression might contribute to the severe immunological symptoms associated with WHIM syndrome.

Keywords

WHIM syndrome; cell migration; chemokine receptors.

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