10 April 2018 Clusters to signal in Molecular Cell

CXCR4 nanocluster size define its dynamics and ability to trigger cell function.

Insights on the mechanisms that govern chemokine receptor nanoscale organization and influence on cell function published in Molecular Cell. Chemokine receptors are crucial for correct migration of cells of the immune system but also involved in autoimmune diseases, tumor progression and metastasis. Researchers Juan Torreño, Carlo Manzo and Enric Gutierrez at the Single Molecule Biophotonics group led by ICREA Professor at ICFO Maria Garcia-Parajo used a combination of single particle tracking and super-resolution microscopy to elucidate the role of spatiotemporal organization on the signaling capacity and function of chemokine receptors. The work performed in collaboration with Laura Martinez-Muñoz and Mario Mellado at CBN-CSIC (Madrid) opens the door for new targets of potential therapeutic intervention in chemokine functions. This work has been recently published in Molecular Cell.

Cell migration is a coordinated process that requires rapid integration of extracellular stimuli and intracellular signaling. Cells migrate towards gradients of chemical stimuli. These “chemoattractants” bind to specific receptors on the cell membrane called chemokine receptors initiating signaling cascades that will activate cells. From the large family of chemokine receptors, CXCR4 and its ligand CXCL12 are involved in development and trafficking of cells of the immune system. Defects in CXCR4 have been associated with tumor progression and metastasis, pulmonary fibrosis, HIV-1 infection and autoimmune diseases amongst others. Although many studies have defined the role of these receptors in chemokine function little is known of their spatiotemporal organization at the cell surface, the factors that participate in their control, or their influence on chemokine biology.

In collaboration with the group of M. Mellado at the CBN in Madrid, the researchers at ICFO used quantitative single-molecule spatiodynamic imaging and super-resolution microscopy to investigate in detail the molecular organization of CXCR4 in human T cells. The results showed that receptor nanoclustering was absolutely necessary for its full function, as cells in which nanoclustering was abolished lacked the capacity to signal and to properly migrate. Importantly, we identified structural motifs of CXCR4 which are responsible for the basal nanoclustering of the receptor and crucial for the formation of large nanoclusters after CXCL12 activation. As the CXCR4/CXCL12 axis is involved in many pathologies, drugs that alter the nanoclustering of this and possibly, of other chemokine receptors, could improve current therapeutic approaches.