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

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, infect...

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Detalles Bibliográficos
Autores: García-Cuesta, Eva M., Rodríguez-Frade, José Miguel, Gardeta, Sofía R., D’Agostino, Gianluca, Martínez, Pablo, Palacios, Blanca Soler, Cascio, Graciela, Wolf, Tobias, Mateos, Nicolas, Ayala-Bueno, Rosa, Santiago, César A., Lucas, Pilar, Llorente, Lucia, Allende, Luis M., González-Granado, Luis Ignacio, Martín-Cófreces, Noa, Roda-Navarro, Pedro, Sallusto, Federica, Sánchez Madrid, Francisco, García-Parajo, María F., Martínez-Muñoz, Laura, Mellado, Mario
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/707702
Acceso en línea:http://hdl.handle.net/10486/707702
https://dx.doi.org/10.1073/pnas.2119483119
Access Level:acceso abierto
Palabra clave:cell migration
chemokine receptors
WHIM syndrome
Medicina
Descripción
Sumario: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

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