Fas ligand is enriched in the caveolae membrane domains of thymic epithelial cells

Lalor, D.J.; Liu, Pingsheng; Hayashi, Jun

doi:10.1016/j.cellimm.2004.08.003

Cited by 5 publications

(3 citation statements)

References 51 publications

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“…Lalor et al 56 reported an almost exclusive localization of FasL in specialized membrane domains, though they detected the ligand in caveolae membrane domains of thymic epithelial cells using a detergent-free separation method for caveolae. Like rafts, caveolae are enriched in sphingolipids and cholesterol, but they form noncoated invaginations of the surface that are substantially bigger than rafts.…”

Section: Discussionmentioning

confidence: 99%

“…Like rafts, caveolae are enriched in sphingolipids and cholesterol, but they form noncoated invaginations of the surface that are substantially bigger than rafts. 29 Despite the copurification of caveolin by Lalor et al, 56 it remains likely that rafts had in fact been isolated together with the caveolae. Our own conclusion that FasL is localized to rafts rather than to caveolae (at least in those cells analyzed by us) is based on the fact that Jurkat cells, in which we detected FasL in detergentresistant membranes, do not contain caveolae.…”

Section: Discussionmentioning

confidence: 99%

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Fas ligand is localized to membrane rafts, where it displays increased cell death–inducing activity

Cahuzac

Baum

Kirkin

et al. 2006

Blood

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Fas ligand (FasL), a member of the TNF protein family, potently induces cell death by activating its matching receptor Fas. Fas-mediated killing plays a critical role in naturally and pathologically occurring cell death, including development and homeostasis of the immune system. In addition to its receptor-interacting and cell death-inducing extracellular domain, FasL has a well-conserved intracellular portion with a proline-rich SH3 domainbinding site probably involved in nonapoptotic functions. We report here that, as with the Fas receptor, a fraction of FasL is constitutively localized in rafts. These dynamic membrane microdomains, enriched in sphingolipids and cholesterol, are important for cell signaling and trafficking processes. We show that FasL is partially localized in rafts and that increased amounts of FasL are found in rafts after efficient FasL/Fas receptor interactions. Raft disorganization after cholesterol oxidase treatment and deletions within the intracellular FasL domain diminish raft partitioning and, most important, lead to decreased FasL killing. We conclude that FasL is recruited into lipid rafts for maximum Fas receptor contact and cell death-inducing potency. These findings raise the possibility that certain pathologic conditions may be treated by altering the cell death-inducing capability of FasL with drugs affecting its raft localization. ( IntroductionThe Fas ligand (FasL, CD95/Apo-1 ligand, CD178, TNFSF6) molecule belongs to the TNF family and potently induces cell death in Fas (CD95/Apo-1/TNFRSF6) receptor-expressing cells. 1 Fas and FasL interact as oligomers, 2 and crosslinking of Fas leads to the recruitment of the adaptor protein FADD and of to the cytoplasmic Fas domain and to the formation of an intracellular receptor complex called death-inducing signaling complex (DISC). 3 Within the DISC, Casp-8 is activated and triggers the downstream caspase cascade, which executes the apoptotic dismantling of the cell.FasL is a type 2 transmembrane protein consisting of a receptor-interacting extracellular domain and a well-conserved 80-amino acid (aa)-long N-terminal cytoplasmic portion. 1,4,5 Cell death initiated by the Fas/FasL system is important for, among others things, homeostasis of the immune system (eg, activationinduced T-cell death 6 ), cytotoxic T cell (CTL)-mediated killing of virally infected or transformed cells, 7 and immune privilege maintenance. [8][9][10][11][12][13][14] The corresponding experimental studies are supported by the pathology of model systems displaying functional inactivation or aberrant activation of Fas/FasL. Mice carrying loss-of-function mutations in the Fas (lpr) or the Fasl (gld) genes develop lymphadenopathy and splenomegaly with a massive accumulation of CD4 Ϫ CD8 Ϫ T cells. 15 In addition, depending on the genetic background, these animals spontaneously acquire various forms of autoimmune disease with high titers of autoantibodies. 16 In humans, mutations in Fas and Fasl are associated with autoimmune lymphoproliferative syndrome (ALPS). [...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fas ligand is localized to membrane rafts, where it displays increased cell death–inducing activity

Cahuzac

Baum

Kirkin

et al. 2006

Blood

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“…A number of key apoptotic signaling molecules have been found in caveolae, such as Fas, tumor necrosis factor receptor 1, Fas-associated death domain protein (FADD), and ceramide (41)(42)(43). Caveolae provide a platform for the assembly of these signaling molecules.…”

Section: Cd8mentioning

confidence: 99%

Caveolin-1 Protects against Sepsis by Modulating Inflammatory Response, Alleviating Bacterial Burden, and Suppressing Thymocyte Apoptosis

Hong

Guo

Song

et al. 2010

Journal of Biological Chemistry

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Sepsis is a leading cause of death, which is characterized by uncontrolled inflammatory response. In this study, we report that caveolin-1, a major component of caveolae, is a critical survival factor of sepsis. We induced sepsis using a well established sepsis animal model, cecal ligation and puncture (CLP). CLP induced 67% fatality in caveolin-1 null mice, but only 27% fatality in wild type littermates (p ‫؍‬ 0.015). Further studies revealed that mice deficient in caveolin-1 exhibited marked increase in tumor necrosis factor-␣ and interleukin-6 production 20 h following CLP treatment, indicating uncontrolled inflammatory responses in the absence of caveolin-1. Caveolin-1 null mice also had a significant increase in bacteria number recovered from liver and spleen, indicating elevated bacterial burdens. In addition, caveolin-1 null mice had a 2-fold increase in thymocyte apoptosis compared with wild type littermates, indicating caveolin-1 as a critical modulator of thymocyte apoptosis during sepsis. In conclusion, our findings demonstrate that caveolin-1 is a critical protective modulator of sepsis in mice. Caveolin-1 exerts its protective function likely through its roles in modulating inflammatory response, alleviating bacterial burdens, and suppressing thymocyte apoptosis.Sepsis is one of the major causes of death, which claims over 215,000 lives and costs $16.7 billion per year in America alone (1-3). The death rate from sepsis is high, exceeding 50%, due to poor understanding of the disease (4). Identifying molecules involved in sepsis, especially endogenous protective modulators, is of great importance, not only in understanding the mechanisms but also in providing new insights for efficient therapies.Caveolae, a subset of lipid rafts, are microdomains of the plasma membrane that are enriched in cholesterol and sphingolipids (5). In addition to its specific lipid compositions, caveolae also contain abundant signaling molecules such as nitricoxide synthase (NOS) 3 and TLR4 and Src family tyrosine kinases, which provide a platform for signal transduction. Caveolin-1, a 24-kDa protein, is a major component of caveolae and has been used as a marker protein of caveolae (6). Disruption of the caveolin-1 gene leads to loss of caveolae (7), indicating an essential role of caveolin-1 in caveolae formation. Given the importance of caveolae in signal transduction, it is not surprising that caveolin-1 has been implicated in a variety of cellular processes such as endocytosis, phagocytosis, and cholesterol trafficking (5-6, 8).Evidence from the caveolin-1 null mouse model has established an inhibitory role of caveolin-1 in cell proliferation and tissue homeostasis. For example, mice deficient in caveolin-1 display hypercellularity in lungs and heart (7, 9 -10). A number of studies also suggest a role of caveolin-1 in apoptosis. However, the role of caveolin-1 in regulating apoptotic cell death is controversial and seems to be cell type-specific and depend on stimuli. For example, knockdown of caveolin-1 by short hairpi...

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Caveolin-1 negatively regulates TRAIL-induced apoptosis in human hepatocarcinoma cells

Zhao

Liu

et al. 2009

Biochemical and Biophysical Research Communications

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Fas ligand is enriched in the caveolae membrane domains of thymic epithelial cells

Cited by 5 publications

References 51 publications

Fas ligand is localized to membrane rafts, where it displays increased cell death–inducing activity

Fas ligand is localized to membrane rafts, where it displays increased cell death–inducing activity

Caveolin-1 Protects against Sepsis by Modulating Inflammatory Response, Alleviating Bacterial Burden, and Suppressing Thymocyte Apoptosis

Caveolin-1 negatively regulates TRAIL-induced apoptosis in human hepatocarcinoma cells

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