Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients

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 CXCR4(R334X), 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 CXCR4(R334X), and their inability to correctly sense chemokine gradients. The underlying mechanisms involve inappropriate actin cytoskeleton remodeling due to the inadequate beta-arrestin1 activation by CXCR4(R334X), 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 beta-arrestin1 to support CXCL12-mediated actin reorganization and receptor clustering. These defects associated with CXCR4(R334X) expression might contribute to the severe immunological symptoms associated withWHIM syndrome.

Automated summary

This study reveals that the truncated mutant chemokine receptor CXCR4(R334X) associated with WHIM syndrome fails to nanoclusterize after CXCL12 stimulation, affecting cell spatial organization and mobility, and causing multiple phalloidin-positive protrusions in cells. The inappropriate activation of beta-arrestin1 by CXCR4(R334X) leads to inadequate actin cytoskeleton remodeling, disrupting the balance between activated and deactivated cofilin.