Integrating High-Resolution Bioimaging Techniques to Unravel How Membrane Lipids Influence Nanoscale Organization and Lateral Mobility of Adhesion Receptors

Abstract

A central, but still unresolved question regarding the function of integrins is how these adhesion receptors regulate both their conformation and dynamic nanoscale organization on the membrane to generate adhesion-competent microclusters upon ligand binding. By superresolution nanoscopy, we recently showed that in quiescent monocytes, LFA-1 preorganizes in ligand-independent nanoclusters proximal to nanoscale raft components (1,2). Furthermore, to dissect the relationship between conformational state, lateral mobility, and microclustering we exploited the high spatial (nanometer) accuracy and temporal resolution of single dye tracking and found that LFA-1 nanoclusters are primarily mobile on the cell surface with a small (ca. 5%) subset of conformational-active LFA-1 nanoclusters preanchored to the cytoskeleton (3).Lateral mobility resulted crucial for the formation of microclusters upon ligand binding and for stable adhesion under shear flow. Ongoing investigation in our laboratory points towards the importance of a specific lipid composition of the membrane nano-environment in modulating LFA-1 biophysical properties which eventually regulate the onset of leukocyte adhesion. Since several (patho)physiological stimuli can alter either temporarily or permanently the plasma membrane lipid composition, our studies offer a novel framework to understand integrin regulation via the lipid nanoenvironment.(1) Van Zanten et al PNAS 2009.(2) Van Zanten et al PNAS 2010.(3) Bakker et al PNAS 2012.