Receptor Mobility is Regulated by the Cytoskeleton Connected to an Exoskeleton via Transmembrane Pickets: Role in Phagocytosis

Abstract

Receptor mobility is regulated by the cytoskeleton connected to an exoskeleton via transmembrane pickets: role in phagocytosis. Phagocytosis is initiated by clustering of receptors upon exposure to target particles bearing multiple ligands. Clustering depends on the ability of receptors to move laterally in the plane of the membrane. Intrinsic proteins were originally thought to diffuse freely along the fluid mosaic of the membrane, but more recent observations indicate that mobility can be severely restricted by the existence of a cytoskeletal fence anchored to the plasmalemma via transmembrane “pickets”. However, the molecular nature of these putative pickets, the manner whereby they associate with the cytoskeleton, and their role in phagocytosis have not been investigated. Based on its abundance and structural features, we surmised that CD44 may serve as a picket in macrophages. We used single-molecule tracking to study its behavior and how it affects the mobility of phagocytic receptors. In addition, because its extracellular domain can bind hyaluronic acid, we found that CD44 serves as a transmembrane connector between the pericellular (glycocalyx) coat, which is akin to an exoskeleton, and the cytoskeleton. The pericellular coat contributes to limit the lateral diffusion of transmembrane proteins and, in addition, restricts access of target particles to phagocytic receptors, which are comparatively short molecules. The implications of this transmembrane structural frame to the phagocytic response will be illustrated and discussed.