The cytoskeleton reduces the diffusional dimensionality of CD36 and promotes its aggregation and signaling

Abstract

We used single‐molecule imaging and single‐particle tracking to investigate the dynamic behavior of CD36, a receptor that mediates oxidized LDL (oxLDL) uptake by macrophages. Free (unliganded) receptors existed as metastable multimers that split and reformed spontaneously. A subpopulation of receptors ( ≈30%) moved in linear patterns radiating from the nucleus. Unexpectedly, the linear motion was not motor‐driven but reflected instead diffusion within a confined space delimited by trough‐like cytoskeletal structures. These were attributed to microtubule‐induced discontinuities in the cortical actin meshwork. The resulting reduction in diffusional dimensionality increased the probability for receptors to collide and aggregate into multimers. CD36 is activated and undergoes endocytosis when clustered by multivalent ligands like oxLDL. Disruption of the cytoskeletal organization reduced multimer formation and inhibited CD36‐mediated signaling and oxLDL internalization. These observations demonstrate that the cytoskeleton can control signal transduction by dictating the confinement of receptors within regions where their collision frequency is increased.