Changes in Cholesterol Level Alter Integrin Sequestration in Raft-Mimicking Lipid Mixtures

Ge, Yifan; Gao, Jiayun; Jordan, Rainer; Naumann, Christoph

doi:10.1016/j.bpj.2017.11.005

Cited by 18 publications

(15 citation statements)

References 59 publications

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“…Both are important T-cell markers that are responsible for the localization of T-cells to the colon [ 19 , 28 ]. It has been shown that different integrins are localized into lipid rafts [ 29 ]. As is the case for the TCR signaling, the membrane structure might be important for these receptors.…”

Section: Discussionmentioning

confidence: 99%

Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation

El-Hindi

Brachtendorf

Hartel

et al. 2020

Cancers

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Ceramide synthase 5 is one of six enzymes that catalyze the production of ceramides from sphingosine or sphinganine. Ceramides are important components of cell membranes and act as signaling molecules. Previously it has been shown that ceramide synthase 6 and 2 influence colitis in several animal models with sometimes opposite effects. Here, we investigated the disease course of dextran sodium sulfate-induced acute colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer in mice with global ceramide synthase 5 knockout (CerS5-ko) or with ceramide synthase 5 knockout restricted to the colon epithelium (CerS5fl/fl VilCre). We monitored disease development and analyzed colon barrier function as well as the immune cell status in these mice. CerS5-ko mice but not CerS5fl/fl-VilCre mice were more susceptible to acute and chronic inflammation. However, the cell barrier function of colon epithelial cells was not disturbed by downregulation of ceramide synthase 5. Instead, untreated CerS5-ko mice displayed reduced numbers of CD3+ immune cells in the spleen, colon, and blood, especially of intraepithelial CD8+ T-cells, which was not obvious in CerS5fl/fl Vil Cre mice. Reduced T-cell number in colon tissue of CerS5-ko mice was accompanied by a reduced expression of IL-1β, IFNγ, and IL-4. In vitro investigations revealed that knockdown of ceramide synthase 5 in T-cells impaired T-cell activation. In summary, we show that CerS5-ko mice were more susceptible to dextran sodium sulfate-induced colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer. A reduced number of T-cells in the colon epithelium that was already the case in untreated CerS5-ko mice might have contributed to this effect.

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Section: Discussionmentioning

confidence: 99%

Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation

El-Hindi

Brachtendorf

Hartel

et al. 2020

Cancers

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“…The integrin family of heterodimeric type 1 transmembrane proteins that facilitate the adhesion of cells to the extra‐cellular matrix (ECM) and to other cells is a prime example of one such regulator 50,51 . Experiments from various groups have demonstrated that the sites of integrin activation such as focal adhesions are associated with membranes with an lo ‐like characteristic 52–54 . Cell detachment resulted in the decrease in membrane order suggesting that integrin ECM attachment regulates this process 55…”

Section: Regulation Of Membrane Domains By “Active” Membrane Moleculesmentioning

confidence: 99%

Toward a new picture of the living plasma membrane

2020

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Our understanding of the plasma membrane structure has undergone a major change since the proposal of the fluid mosaic model of Singer and Nicholson in the 1970s. In this model, the membrane, composed of over thousand lipid and protein species, is organized as a well-equilibrated two-dimensional fluid.Here, the distribution of lipids is largely expected to reflect a multicomponent system, and proteins are expected to be surrounded by an annulus of specialized lipid species. With the recognition that a multicomponent lipid membrane is capable of phase segregation, the membrane is expected to appear as patchwork quilt pattern of membrane domains. However, the constituents of a living membrane are far from being well equilibrated. The living cell membrane actively maintains a trans-bilayer asymmetry of composition, and its constituents are subject to a number of dynamic processes due to synthesis, lipid transfer as well as membrane traffic and turnover. Moreover, membrane constituents engage with the dynamic cytoskeleton of a living cell, and are both passively as well as actively manipulated by this engagement. The extracellular matrix and associated elements also interact with membrane proteins contributing to another layer of interaction. At the nano-and mesoscale, the organization of lipids and proteins emerge from these encounters, as well as from protein-protein, protein-lipid, and lipid-lipid interactions in the membrane. New methods to study the organization of membrane components at these scales have also been developed, and provide an opportunity to synthesize a new picture of the living cell surface as an active membrane composite.actin binding proteins, actin cytoskeleton, fluid mosaic model, GPI-anchored proteins, mesoscale organization, nanoclustering, picket fence model, plasma membrane, plasma membrane organization, transmembrane proteins

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“…Integrin sequestration changes are also dependent on cholesterol concentrations in lipid rafts [ 113 ]. Ligands and bilayer asymmetry influence the sequestering of integrin into rafts and suggest a role of lipid packing and bilayer thickness that characterize the liquid-ordered and liquid-disordered domains in integrin sequestering.…”

Section: The Role Of Cholesterolmentioning

confidence: 99%

“…Recent data showed that systematic changes in the membrane cholesterol concentration impact the sequestration of integrin αVβ3 in coexisting liquid-ordered and liquid-disordered domains, thus being qualitatively distinct in sequestering in the absence and presence of its native ligand vitronectin [ 113 ]. Nevertheless, the role of cholesterol in integrin sequestration and recruitment during lipid membrane raft-mediated integrin signaling and adhesions remains poorly understood, perhaps partly due to the small size and transient nature of raft domains [ 22 , 114 ].…”

Section: The Role Of Cholesterolmentioning

confidence: 99%

“…Mixtures of cholesterol, 1,2-dioleoyl- sn -glycero-3-phosphocholine, and dipalmitoylphosphatidylcholine form coexisting liquid-ordered and liquid-disordered domains, whereby molar concentrations influence integrin αVβ3 sequestration regardless of its ligand vitronectin and without clustering [ 113 ]. Significantly, focal adhesions have high concentrations of cholesterol [ 108 ] and can thus play a role in regulating integrin function [ 16 ].…”

Section: Integrin-glycosphingolipids Interactionsmentioning

confidence: 99%

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Roles of Membrane Domains in Integrin-Mediated Cell Adhesion

Lietha

Izard

2020

IJMS

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The composition and organization of the plasma membrane play important functional and regulatory roles in integrin signaling, which direct many physiological and pathological processes, such as development, wound healing, immunity, thrombosis, and cancer metastasis. Membranes are comprised of regions that are thick or thin owing to spontaneous partitioning of long-chain saturated lipids from short-chain polyunsaturated lipids into domains defined as ordered and liquid-disorder domains, respectively. Liquid-ordered domains are typically 100 nm in diameter and sometimes referred to as lipid rafts. We posit that integrin β senses membrane thickness and that mechanical force on the membrane regulates integrin activation through membrane thinning. This review examines what we know about the nature and mechanism of the interaction of integrins with the plasma membrane and its effects on regulating integrins and its binding partners.

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Changes in Cholesterol Level Alter Integrin Sequestration in Raft-Mimicking Lipid Mixtures

Cited by 18 publications

References 59 publications

Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation

Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation

Toward a new picture of the living plasma membrane

Roles of Membrane Domains in Integrin-Mediated Cell Adhesion

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