1. Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients.
- Author
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García-Cuesta, Eva M., Rodńguez-Frade, José Miguel, Gardeta, Sofía R., D'Agostino, Gianluca, Martınez, Pablo, Soler Palacios, Blanca, Cascio, Graciela, Wolf, Tobias, Mateos, Nicolas, Ayala-Bueno, Rosa, Santiago, César A., Lucas, Pilar, Llorente, Lucia, Allende, Luis M., Ignacio González-Granadog, Luis, Martín-Cófreces, Noa, Roda-Navarro, Pedro, Sallusto, Federica, Sánchez-Madridi, Francisco, and Garc&ía-Parajoe, Marńa F.
- Subjects
CXCR4 receptors ,CELL migration ,CHEMOKINE receptors ,LABOR mobility ,CYTOSKELETON ,CELL physiology - 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 ß-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 ß-arrestin1 to support CXCL12-mediated actin reorganization and receptor clustering. These defects associated with CXCR4R334X expression might contribute to the severe immunological symptoms associated withWHIM syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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