Proc Natl Acad Sci U S A. 2022 May 24;119(21):e2119483119.
Eva M García-Cuesta , José Miguel Rodríguez-Frade , Sofía R Gardeta, Gianluca D'Agostino, Pablo Martínez, Blanca Soler Palacios , Graciela Cascio , Tobias Wolf Nicolas Mateos, Rosa Ayala-Bueno , César A Santiago, Pilar Lucas, Lucia Llorente, Luis M Allende Luis Ignacio González-Granado, Noa Martín-Cófreces, Pedro Roda-Navarro 7 12 , Federica Sallusto, Francisco Sánchez-Madrid, María F García-Parajo, Laura Martínez-Muñoz Mario Mellado
Abstract
SignificanceNew imaging-based approaches are incorporating new concepts to our knowledge of biological processes. The analysis of receptor dynamics involved in cell movement using single-particle tracking demonstrates that cells require chemokine-mediated receptor clustering to sense appropriately chemoattractant gradients. Here, we report that this process does not occur in T cells expressing CXCR4R334X, a mutant form of CXCR4 linked to WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis). The underlaying molecular mechanism involves inappropriate actin cytoskeleton remodeling due to the inadequate β-arrestin1 activation by CXCR4R334X, which alters its lateral mobility and spatial organization. These defects, associated to CXCR4R334X expression, contribute to the retention of hematopoietic precursors in bone marrow niches and explain the severe immunological symptoms associated with WHIM syndrome.
doi: 10.1073/pnas.2119483119.