Article
Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients
Author/s | García Cuesta, Eva M.
Rodríguez Frade, José Miguel Gardeta, Sofía R. D'Agostino, Gianluca Martínez, Pablo Soler Palacios, Blanca Martínez Muñoz, Laura Mellado, Mario |
Department | Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología |
Publication Date | 2022 |
Deposit Date | 2023-04-17 |
Published in |
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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 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 nanoclus terize 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 chemo kine 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 asso ciated with WHIM syndrome. |
Funding agencies | Ministerio de Ciencia e Innovación |
Project ID. | PID2020- 114980RB-I00 |
Citation | García Cuesta, E.M., Rodríguez Frade, J.M., Gardeta, S.R., D'Agostino, G., Martínez, P., Soler Palacios, B.,...,Mellado, M. (2022). Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 19 (21), e2119483119. https://doi.org/10.1073/pnas.2119483119. |
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