21 July 2014 The advantages of order in Biology

Glycan-mediated micro-patterning of the cell membrane showing DC-SIGN nanoclusters (red) being confined in clathrin (green) enriched areas.

Cell membranes exploit hierarchical order to efficiently internalize pathogens in PNAS. A recent study carried out by Juan Torreno-Pina, Bruno Castro and Carlo Manzo of the Single Molecule Biophotonics group led by ICREA Professor at ICFO María García-Parajo, established a crucial role for the organization of the cell membrane in the recognition and binding of pathogens. The study reveals that pathogen recognition receptors organize in a highly hierarchical fashion on the membrane of immune cells (from the nano- to the meso-scale) exploring regions that are enriched with sites for endocytosis. This preferred organization increases the probability of internalizing virus pathogens for subsequent processing and degradation by dendritic cells. This work, carried out in collaboration with a team of scientists from the Radboud University Medical Center in Nijmegen, the Netherlands, has been published in PNAS.

Dendritic cells are the first line of fighters in our body against infections and foreigner pathogens. These cells are equipped with a battery of receptors designed to recognize and take in pathogens for further degradation. Amongst them, the pathogen recognition receptor DC-SIGN does this job with amazing efficiency and versatility. Previous work from Garcia-Parajo´s Lab found that organization of this receptor in small nanoclusters was crucial for binding DC-SIGN to viruses, including HIV. Other molecules called glycans (sugars with different branching structures) which are ubiquitously present in the cell membrane, have the potential to interact with glycosylated proteins such as DC-SIGN, but until now their role on DC-SIGN was completely unknown.

Using a combination of superresolution imaging techniques and dual-color single-particle tracking, ICFO researchers visualized the spatiotemporal organization of DC-SIGN on cells of the immune system. Intriguingly, glycans micro-patterned the receptor in regions of around 1 m in size. In turn, this micro-patterning corralled DC-SIGN into clathrin active regions (the primary internalization pathway in mammalian cells). Using a newly developed single molecule dynamic approach, ICFO researchers saw increasing clathrin–receptor interactions and enhanced clathrin-mediated endocytosis of virus-like particles bound to DC-SIGN.

Understanding how the cells of our immune system recognize and fight against pathogens is of key importance to human health. This work demonstrates that efficient pathogen binding and uptake crucially depends on how receptors organize on the cell membrane, providing clear guidelines for the design of new therapeutic drugs against infections. It is also a clear example on how Nature has devised strategies to optimize cellular function using concepts of compartmentalization and molecular modularity.