RT Journal Article T1 Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients. A1 García-Cuesta, Eva M A1 Rodríguez-Frade, José Miguel A1 Gardeta, Sofía R A1 D'Agostino, Gianluca A1 Martínez, Pablo A1 Soler Palacios, Blanca A1 Cascio, Graciela A1 Wolf, Tobias A1 Mateos, Nicolas A1 Ayala-Bueno, Rosa A1 Santiago, César A A1 Lucas, Pilar A1 Llorente, Lucia A1 Allende, Luis M A1 González-Granado, Luis Ignacio A1 Martín-Cófreces, Noa A1 Roda-Navarro, Pedro A1 Sallusto, Federica A1 Sánchez-Madrid, Francisco A1 García-Parajo, María F A1 Martínez-Muñoz, Laura A1 Mellado, Mario K1 WHIM syndrome K1 cell migration K1 chemokine receptors AB 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. YR 2022 FD 2022-05-19 LK http://hdl.handle.net/10668/19666 UL http://hdl.handle.net/10668/19666 LA en DS RISalud RD Apr 10, 2025