Targeting CD4 to Disrupt Signaling Through Membrane Rafts: Towards a Raft-Based Therapeutics

Abstract

Membrane rafts, due to the presence of several immunoreceptors, signal-transducing kinases and lipids such as ceramides which can act as second messengers, play a crucial role in the cell signaling network which fine-tunes various biological effects. The ability of membrane rafts to segregate receptors provides a mechanism for compartmentalization of signaling molecules in plasma membrane by concentrating some components in membrane rafts and excluding others. Based on these observations, the concept of raft-based therapeutics has recently emerged. Raft-targeting molecules can modulate the lipid-protein rheostat of membrane rafts to treat various diseases, such as cancer, neurological disorders or infectious diseases. In this review, we focus on membrane rafts as "discrete" organizing elements of T lymphocytes' plasma membrane and how to reconcile the dynamic nature of membrane rafts with the formation of the immunological synapse. We describe CD4-specific antibodies as prototypical modulators for the disruption of the lipid-protein rheostat in membrane rafts and extend the concept of raft-based therapeutics to other antibodies, sterol-and sphingolipid-modulating drugs, glycerophospholipid analogs, fatty acid modulators, and peptide-derived molecules. This review highlights a novel mode of action of drugs through dietary or therapeutic interventions that target membrane rafts.

The lipid-modulating effects of a CD4-specific recombinant antibody correlate with ZAP-70 segregation outside membrane rafts

“…In vivo therapeutic synergy between rituximab and lipids modulators, such as fenretinide [11,12] and aplidine [13], has been demonstrated, thus leading to the idea of combining lipid modulators and antibodies, as proposed in a combinatorial phase I/II clinical trial in B cell lymphoma (trial NCT00288067). Altogether, these results clearly emphasized a dynamic crosstalk between sphingolipids/cholesterol and proteins (lipid-protein "rheostat") in membrane rafts that can be modulated by antibodies [5].…”

“…Cholesterol/sphingolipids confer organization of membrane rafts through self-assembly but could also be incorporated in the quaternary structure of raft-located protein complexes ("lubrication" concept) [2], thus favoring their inclusion into and the assembly of functionalized membrane rafts. They play a major role in the modulation of apoptosis [3] and cell growth [4], and their targeting represents an attractive strategy of raft-based therapeutics [5,6]. Indeed, cholesterol sequesters and inhibitors of cholesterol synthesis as well as sphingolipid-modulating drugs, which mainly act on enzymes involved in ceramide metabolism [5], regulate cell growth, differentiation, stress response and apoptosis [7].…”

“…They play a major role in the modulation of apoptosis [3] and cell growth [4], and their targeting represents an attractive strategy of raft-based therapeutics [5,6]. Indeed, cholesterol sequesters and inhibitors of cholesterol synthesis as well as sphingolipid-modulating drugs, which mainly act on enzymes involved in ceramide metabolism [5], regulate cell growth, differentiation, stress response and apoptosis [7]. Ceramide accumulation occurs through two main pathways: hydrolysis from sphingomyelin through sphingomyelinase (SMase) stimulation and de novo synthesis by ceramide synthase activation.…”