CD95 Structure, Aggregation and Cell Signaling

Levoin, Nicolas; Jean, Mickaël; Legembre, Patrick

doi:10.3389/fcell.2020.00314

Cited by 32 publications

(29 citation statements)

References 101 publications

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“…The non-apoptotic pathways that utilise Fas activating signals are, in general, poorly understood, despite evidence about the cell-death independent activities of the Fas/FasL complex accumulating [ 5 , 46 , 47 , 48 , 49 ]. The possible downstream mechanism triggering FasL signalling towards the apoptotic vs. the non-apoptotic fate is not known.…”

Section: Discussionmentioning

confidence: 99%

“…The possible downstream mechanism triggering FasL signalling towards the apoptotic vs. the non-apoptotic fate is not known. The Fas receptor has no enzymatic activity; therefore, mechanisms such as fine-tuned control of its aggregation/conformation, post-translational modifications, or changes in the distribution pattern within the membrane are being considered [ 48 , 49 ]. Interference with NF-kB signalling is another option; however, the data are still controversial.…”

Section: Discussionmentioning

confidence: 99%

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Impact of FasL Stimulation on Sclerostin Expression and Osteogenic Profile in IDG-SW3 Osteocytes

Kratochvílová

Ramesova

Veselá

et al. 2021

Biology

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The Fas ligand (FasL) is known from programmed cell death, the immune system, and recently also from bone homeostasis. As such, Fas signalling is a potential target of anti-osteoporotic treatment based on the induction of osteoclastic cell death. Less attention has been paid to osteocytes, although they represent the majority of cells within the mature bone and are the key regulators. To determine the impact of FasL stimulation on osteocytes, differentiated IDG-SW3 cells were challenged by FasL, and their osteogenic expression profiles were evaluated by a pre-designed PCR array. Notably, the most downregulated gene was the one for sclerostin, which is the major marker of osteocytes and a negative regulator of bone formation. FasL stimulation also led to significant changes (over 10-fold) in the expression of other osteogenic markers: Gdf10, Gli1, Ihh, Mmp10, and Phex. To determine whether these alterations involved caspase-dependent or caspase-independent mechanisms, the IDG-SW3 cells were stimulated by FasL with and without a caspase inhibitor: Q-VD-OPh. The alterations were also detected in the samples treated by FasL along with Q-VD-OPh, pointing to the caspase-independent impact of FasL stimulation. These results contribute to an understanding of the recently emerging pleiotropic effects of Fas/FasL signalling and specify its functions in bone cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impact of FasL Stimulation on Sclerostin Expression and Osteogenic Profile in IDG-SW3 Osteocytes

Kratochvílová

Ramesova

Veselá

et al. 2021

Biology

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“…Alternatively, it is also possible that sFasL plays a more active role in immunomodulation. Studies from Legembre and colleagues have shown that naturally cleaved sFasL can engage Fas and activate a PLCg1→PI3K→Akt pathway associated with cell survival, induction of T cell motility, and tumor invasion 80,92,156,157 . To what extent sFasL actively regulates the inflammatory process in glaucoma and other ocular disorders remains an area of active investigation that has important implications for therapeutic applications of sFasL.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

The FasLane to ocular pathology—metalloproteinase cleavage of membrane-bound FasL determines FasL function

Gregory-Ksander

Marshak‐Rothstein

2021

Journal of Leukocyte Biology

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Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas‐expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane‐associated FasL (mFasL) and the C‐terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti‐apoptotic and anti‐inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.

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“…The control of the potentially limitless expansion of activated T cells is primarily achieved by activation of the death receptor Fas (CD95/Apo-1) [ 7 ]. Fas is a cell surface glycoprotein that triggers apoptosis upon binding to its cognate ligand, Fas Ligand (FasL/CD95L), or when experimentally activated by specific agonistic antibodies [ 8 ]. Excessive Fas/FasL-mediated apoptosis resulting from abnormal activation and proliferation of T cells has a negative impact in the surrounding tissues, leading to immune-mediated injury.…”

Section: Introductionmentioning

confidence: 99%

E2f2 Attenuates Apoptosis of Activated T Lymphocytes and Protects from Immune-Mediated Injury through Repression of Fas and FasL

Mustafa

Mitxelena

Infante

et al. 2021

IJMS

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Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, E2f2−/− mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine E2f2−/− T cells overexpress the proapoptotic genes Fas and FasL and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated E2f2−/− lymphocytes, but targeted disruption of p53 in E2f2−/− mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to Fas and FasL gene promoters to repress their expression. in vivo, E2f2−/− mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies.

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CD95 Structure, Aggregation and Cell Signaling

Cited by 32 publications

References 101 publications

Impact of FasL Stimulation on Sclerostin Expression and Osteogenic Profile in IDG-SW3 Osteocytes

Impact of FasL Stimulation on Sclerostin Expression and Osteogenic Profile in IDG-SW3 Osteocytes

The FasLane to ocular pathology—metalloproteinase cleavage of membrane-bound FasL determines FasL function

E2f2 Attenuates Apoptosis of Activated T Lymphocytes and Protects from Immune-Mediated Injury through Repression of Fas and FasL

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