Membrane Compartmentalization and Scaffold Proteins in Leukocyte Migration

Abstract

Leukocyte migration across vessels into and within peripheral and lymphoid tissues is essential for host defense against invading pathogens. Leukocytes are specialized in sensing a variety of guidance cues and to integrate environmental stimuli to navigate in a timely and spatially controlled manner. These extracellular signals must be transmitted across the leukocyte's plasma membrane in a way that intracellular signaling cascades enable directional cell movement. Therefore, the composition of the membrane in concert with proteins that influence the compartmentalization of the plasma membrane or contribute to delineate intracellular signaling molecules are key in controlling leukocyte navigation. This becomes evident by the fact that mislocalization of membrane proteins is known to deleteriously affect cellular functions that may cause diseases. In this review we summarize recent advances made in the understanding of how membrane cholesterol levels modulate chemokine receptor signaling and hence leukocyte trafficking. Moreover, we provide an overview on the role of membrane scaffold proteins, particularly tetraspanins, flotillins/reggies, and caveolins in controlling leukocyte migration both in vitro and in vivo.

Keywords: caveolin; flotillin/reggie; leukocyte migration; membrane compartmentalization; scaffold proteins; tetraspanin.

FIGURE 1

Schematic representation of a chemokine receptor and its associated heterotrimeric G-protein. Chemokine receptors belong to the GPCR family and possess seven-transmembrane domains. Chemokines initiate chemokine receptor activation by binding to the N-terminus and extracellular loops of the receptor. Once the chemokine is tethered to the receptor, the N-terminus enters the binding pocket where it interacts with the transmembrane domains of the chemokine receptor. The presence of cholesterol is critical for the stability of the chemokine receptor. Upon ligand binding, the receptor promotes the exchange of GDP for GTP on the Gα-subunit, resulting in the dissociation of the Gα- from the Gβγ-subunits and downstream signaling. The Gα- and Gγ-subunits are post-transcriptionally lipidated facilitating their association with the plasma membrane.

FIGURE 2

Schematic representation of flotillin, tetraspanin, and caveolin in the lipid bilayer. Flotillins are associated at the cytosolic leaflet of the plasma membrane through its N-terminal PHB domain. Membrane association is further assured through myristoylation (green) and palmitoylation (red). Flotillins form hetero-mers through specialized intracellular flotillin domains. Tetraspanins are composed of four transmembrane α-helices and two extracellular domains: the SEL (small extracellular loop) and the LEL (large extracellular loop). Tetraspanins are palmitoylated at a conserved CXXC motif in their transmembrane domains. Caveolins form hairpin loops that are inserted into the plasma membrane. Both N- and C-termini face the cytoplasmic side of the membrane.