The extracellular glycosphingolipid-binding motif of Fas defines its internalization route, mode and outcome of signals upon activation by ligand

Chakrabandhu, Krittalak; Huault, Sébastien; Garmy, Nicolas; Fantini, Jacques; E, Stebe; Mailfert, Sébastien; Marguet, Didier; Ao, Hueber

doi:10.1038/cdd.2008.115

Cited by 57 publications

(54 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ezrin-actin association is reported to be required for endocytosis of Fas in mouse embryonic fibroblasts and L12.10 cells (Piazzolla et al, 2005;Chakrabandhu et al, 2007Chakrabandhu et al, , 2008. We found that Fas internalization in H9 cells ( Figure 6) was similar in efficiency to that documented elsewhere (Piazzolla et al, 2005;Lee et al, 2006;Chakrabandhu et al, 2007).…”

Section: Discussionsupporting

confidence: 80%

“…However, deficiency in ezrin did not affect endocytosis of Fas in H9 cells, suggesting that the observed enhanced DISC formation (Figure 7) was not due to altered internalization of Fas. Discrepancies in the involvement of ezrin in Fas endocytosis between this study and others (Piazzolla et al, 2005;Chakrabandhu et al, 2007Chakrabandhu et al, , 2008 may be due to differences between T cells and L cell/fibroblasts, because the function of ERM is highly cell type dependent (Bretscher et al, 2002;Niggli and Rossy, 2008). However, just why ezrin is required for Fas endocytosis in L cells/fibroblasts but not in T cells remains to be elucidated.…”

Section: Discussioncontrasting

confidence: 51%

“…The downregulation of ezrin in CEM cells abolishes their susceptibility to Fas-induced apoptosis (Parlato et al, 2000), and the knockdown of ezrin or moesin in Jurkat cells decreases Fas-triggered apoptosis (He´bert et al, 2008). It has also been shown that Fasezrin-actin linkage is involved in Fas endocytosis, and Fas-induced apoptosis was attenuated in ezrin-knockdown L12.10 cells (Chakrabandhu et al, 2007(Chakrabandhu et al, , 2008. Therefore, the exact role of ezrin in death receptorinitiated apoptosis remains unsettled.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ezrin is a negative regulator of death receptor-induced apoptosis

et al. 2009

View full text Add to dashboard Cite

Ezrin links cortical actin filaments with the cell membrane, and has a critical role in many membrane-initiated events. Fas is directly associated with ezrin, but conflicting results have been reported for the involvement of ezrin in Fas-induced cell death. In this study we show that ezrin was associated with Fas in T cells before stimulation and was released shortly after Fas ligand (FasL) engagement. The knockdown of ezrin moderately increased Fastriggered or tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-triggered cell death in normal T lymphocytes and in H9 cells, but had no effect on death receptor-induced apoptosis in type II cells, such as Jurkat and CEM. Expression of a dominant-negative form of ezrin also led to an increased Fas-induced apoptosis in H9 cells. Ezrin deficiency did not affect the internalization of Fas after Fas ligation. Instead, an enhanced formation of death-inducing signaling complex (DISC) was observed in H9 cells with ezrin knockdown, leading to accelerated caspase-8 activation. Together, our results suggest that ezrin has a negative role in the recruitment of Fas into signaling complexes in type I T cells. Loss of ezrin likely removes the constraint imposed by ezrin and facilitates the assembly of death receptor complex in T cells.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Discussioncontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ezrin is a negative regulator of death receptor-induced apoptosis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Notably, an ezrin-dependent route of internalization was recently described to counteract cell death induction and promote antiapoptotic functions of CD95. 21 Interestingly in this context, in contrast to CD95-mediated cell death induction, CD95 localization in raft nanodomains has very recently been shown to be dispensable for non-apoptotic CD95 internalization and signaling. 22 Our own analyses suggest an accelerated actin-dependent CD95/TCR co-internalization as a mechanism to establish receptor interference and signaling crosstalk.…”

Section: Modulation Of Primary T-cell Activation By Cd95mentioning

confidence: 99%

Modulation of CD4+ T-cell activation by CD95 co-stimulation

et al. 2010

View full text Add to dashboard Cite

CD95 is a dual-function receptor that exerts pro-or antiapoptotic effects depending on the cellular context, the state of activation, the signal threshold and the mode of ligation. In this study, we report that CD95 engagement modulates TCR/CD3-driven signaling pathways in resting T lymphocytes in a dose-dependent manner. While high doses of immobilized CD95 agonists silence T cells, lower concentrations augment activation and proliferation. We analyzed the co-stimulatory capacity of CD95 in detail in resting human CD4 þ T cells, and demonstrate that low-dose ligand-induced co-internalization of CD95 and TCR/CD3 complexes enables non-apoptotic caspase activation, the prolonged activation of MAP kinases, the upregulation of antiapoptotic proteins associated with apoptosis resistance, and the activation of transcription factors and cell-cycle regulators for the induction of proliferation and cytokine production. We propose that the levels of CD95L on antigen-presenting cells (APCs), neighboring T cells or epithelial cells regulate inhibitory or co-stimulatory CD95 signaling, which in turn is crucial for fine-tuning of primary T-cell activation. Cell Death and Differentiation (2011) 18, 619-631; doi:10.1038/cdd.2010.134; published online 5 November 2010For activation of resting T cells, two signals are required. The first signal emerges from an engagement of the T cell receptor (TCR)/CD3 complex, whereas the second signal is generated through the ligation of co-stimulatory receptors (i.e. CD28). Recently, 'tumor necrosis factor (TNF) receptor-associated factor' (TRAF) binding receptors were identified as a second class of co-stimulatory receptors. 1 As an example, Alderson et al. 2,3 provided first evidence for the role of CD95 (Fas, APO-1), the prototypic death receptor of the immune system, in the activation of human T cells. It was subsequently reported that CD3-crosslinking alone or CD3/CD95 costimulation induces the processing of caspase-8 and/or caspase-3 as a prerequisite for full T-cell proliferation. [4][5][6] CD95 co-ligation also influences several other routes of intracellular signal transduction. Kataoka et al. 7 reported the activation of NF-kB-and mitogen-activated protein kinase (MAPK)-related pathways following an interaction of CD95-recruited 'cellular FLICE-inhibitory protein' (cFLIP) with downstream signaling molecules. Apparently, this process required the cleavage of cFLIP into a p43 fragment. More recently, however, it was argued that p22-FLIP (but not p43) can activate NF-kB by directly interacting with the IKK complex. 8 So far, three cFLIP isoforms (cFLIP L , cFLIP S and cFLIP R ) were identified, with cFLIP S/R mediating a block in apoptosis by inhibiting procaspase-8 at the death-inducing signaling complex (DISC). The role of cFLIP L regarding an inhibition at the DISC is still a matter of debate. 8,9 Further downstream, antiapoptotic proteins including Bcl-2/Bcl-X L and 'X-linked inhibitor-of-apoptosis protein' (XIAP) may prevent apoptosis. 9,10 A decreased expression of antiapoptotic c...

show abstract

“…The group of Hueber et al identified a putative glycosphingolipid-binding motif (GBM) in the extracellular part of CD95 that regulates the dynamics and aggregation of CD95 within the detergent-resistant raft fraction (Chakrabandhu et al, 2008). In this study, CD95 mutants with a defect in this motif were severely affected in their ability to recruit FADD and caspase 8 and to trigger apoptosis but showed normal recruitment of ezrin (Chakrabandhu et al, 2008).…”

Section: Interaction Of Cd95 With the Actin Cytoskeleton And Internalmentioning

confidence: 73%

Principles and mechanisms of CD95 activation

Wajant

2014

Biological Chemistry

View full text Add to dashboard Cite

CD95 (Apo1/Fas) has been originally identified as the target of cell death-inducing antibodies. The recognition of CD95 as an apoptosis-triggering receptor represents one of the early milestones in the apoptosis field. Moreover, the research on CD95-induced cell death fostered various other discoveries of broad and general relevance in cell biology, for example, the identification of caspase 8 as the initiator caspase of the extrinsic apoptosis pathway. Activation of CD95-associated intracellular signaling pathways is not a simple consequence of ligand binding but is the fine-tuned result of a complex interplay of various molecular mechanisms that eventually determine the strength and quality of the CD95 response. There is growing evidence that different forms of CD95 stimulation trigger the assembly of CD95 signaling complexes of distinct composition. Moreover, the formation of signaling competent CD95 complexes is a multistep process and the subject of regulation by various cellular cues. This review addresses the relevance of the molecular nature of the CD95-stimulating agonist for the quality of the CD95 response and discusses the importance of modification, clustering, internalization, and lipid raft and actin association of CD95 for CD95 activity.

show abstract

The extracellular glycosphingolipid-binding motif of Fas defines its internalization route, mode and outcome of signals upon activation by ligand

Cited by 57 publications

References 40 publications

Ezrin is a negative regulator of death receptor-induced apoptosis

Ezrin is a negative regulator of death receptor-induced apoptosis

Modulation of CD4+ T-cell activation by CD95 co-stimulation

Principles and mechanisms of CD95 activation

Contact Info

Product

Resources

About