Ezrin is a negative regulator of death receptor-induced apoptosis

Abstract

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.

Syntenin-1 and Ezrin Proteins Link Activated Leukocyte Cell Adhesion Molecule to the Actin Cytoskeleton

“…The engagement of ALCAM with CD6 on the T cells could therefore contribute to this process by allowing the formation of a stable nucleation site for further actin polymerization to strengthen the cell-cell interaction. In addition, in T cells ezrin has been shown to be a negative regulator of death receptor-induced apoptosis (63). The enrichment of ezrin in the ALCAM supramolecular assembly at the DC side could provide another survival signal to the DCs.…”

New mechanisms for old drugs: Insights into DNA-unrelated effects of platinum compounds and drug resistance determinants

“…For instance, cisplatin has been described to promote the inactivation of ezrin (EZR), a cytoskeletal protein with scaffold functions implicated in the signal transduction from membrane receptors (Neisch and Fehon, 2011;Zeidan et al, 2008). Importantly, EZR brings together CD95/Fas and the actin cytoskeleton, allowing an interaction that needs to be broken for death receptor-induced apoptosis (Fais et al, 2005;Kuo et al, 2010). The cytoskeletal destabilization induced by Pt complexes further contributes to the cellular injuries leading to cell death, because several components of the cytoskeleton are able to deliver a pro-apoptotic signal in response to perturbations of the microtubular or actin network (Galluzzi et al, 2014a,b).…”

Removal of Syndecan-1 Promotes TRAIL-Induced Apoptosis in Myeloma Cells

“…The eluent was resolved by SDS-PAGE and probed with Abs for DR4, DR5, caspase-8 (Cell Signaling), FADD, and b-tubulin. DISC precipitation in H9 cells using FLAG-FasL and anti-FLAG beads was performed, as previously described (30).…”