Changes in membrane sphingolipid composition modulate dynamics and adhesion of integrin nanoclusters

Abstract

Sphingolipids are essential constituents of the plasma membrane (PM) and play an important role in signal transduction by modulating clustering and dynamics of membrane receptors. Changes in lipid composition are therefore likely to influence receptor organisation and function, but how this precisely occurs is difficult to address given the intricacy of the PM lipid-network. Here, we combined biochemical assays and single molecule dynamic approaches to demonstrate that the local lipid environment regulates adhesion of integrin receptors by impacting on their lateral mobility. Induction of sphingomyelinase (SMase) activity reduced sphingomyelin (SM) levels by conversion to ceramide (Cer), resulting in impaired integrin adhesion and reduced integrin mobility. Dual-colour imaging of cortical actin in combination with single molecule tracking of integrins showed that this reduced mobility results from increased coupling to the actin cytoskeleton brought about by Cer formation. As such, our data emphasizes a critical role for the PM local lipid composition in regulating the lateral mobility of integrins and their ability to dynamically increase receptor density for efficient ligand binding in the process of cell adhesion.

Ceramide and palmitic acid inhibit macrophage-mediated epithelial–mesenchymal transition in colorectal cancer

“…Thus, macrophage function and phenotype are highly dependent on their microenvironment [40]. Lipids (cellular or dietary) and alterations in lipid metabolism have long been identified as regulators of immune cell function and macrophage polarization [27,[41][42][43][44]. Consistent with previous reports, our data demonstrate that PA and Cer attenuate the M2-phenotype in macrophages.…”

“…In addition, macrophage can accumulate lipids intracellularly via scavenger receptors, and cause endoplasmatic stress and mitochondrial dysfunction, which drives the M1 phenotype and inflammatory response [26]. Cer, a sphingolipid metabolite, plays an important role in many pathobiological processes, such as growth arrest, apoptosis, cellular signaling adhesion, and trafficking of immune cells [41,46]. Cer is also a powerful tumor suppressor, and has recently been shown to induce anti-tumor immunity by targeting M2-TAMs through inhibition of ROS signaling [36].…”

“…Lipids, such as PA and Cer are components of the plasma membrane. Changes in Cer levels in the plasma membrane of immune cells have been shown to affect plasma membrane composition and compartmentalization [41] and signaling pathways, such as PI3 kinase-Akt pathway [50]. Addition of PA and Cer might affect macrophage plasma membrane properties and thereby alter the signaling pathways underlying M2-TAM polarization, resulting in a different cytokine profile, marker expression, and morphology.…”

Regulation of Arthritis Severity by the Acid Sphingomyelinase

“…Similarly, endothelial Asm may regulate lymphocyte extravasation in synovial micro-vessels. Enhanced cell adhesion upon sphingomyelinase- or ceramide treatment has been reported in different cell types, hinting at a general mechanism [50-52]. Particularly relevant to this study are reports on hematogenous metastasis, indicating that platelets secrete Asm to regulate tumor cell extravasation [51].…”

Biomechanical control of lysosomal secretion via the VAMP7 hub: a tug-of-war mechanism between VARP and LRRK1

“…Interestingly enough, VAMP7 was shown to play an essential role in cell migration and invasion (Proux-Gillardeaux et al, 2007; Steffen et al, 2008; Williams and Coppolino, 2011). VAMP7 also contributes into the regulation of membrane composition of sphingolipids and GPI-anchored protein (Molino et al, 2015), which in turn modulates integrin dynamic and adhesion (Eich et al, 2016; van Zanten et al, 2009).…”