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 Martínez, Luis Miguel
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
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.
PB National Academy of Sciences
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/120087
UL https://hdl.handle.net/20.500.14352/120087
LA eng
NO García-Cuesta EM, Rodríguez-Frade JM, Gardeta SR, D'Agostino G, Martínez P, Soler Palacios B, Cascio G, Wolf T, Mateos N, Ayala-Bueno R, Santiago CA, Lucas P, Llorente L, Allende LM, González-Granado LI, Martín-Cófreces N, Roda-Navarro P, Sallusto F, Sánchez-Madrid F, García-Parajo MF, Martínez-Muñoz L, Mellado M. 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. Epub 2022 May 19. PMID: 35588454; PMCID: PMC9173760.
DS Docta Complutense
RD 18 dic 2025