Regulation of CD95/Fas signaling at the DISC

Abstract

CD95 (APO-1/Fas) is a member of the death receptor (DR) family. Stimulation of CD95 leads to induction of apoptotic and non-apoptotic signaling pathways. The formation of the CD95 death-inducing signaling complex (DISC) is the initial step of CD95 signaling. Activation of procaspase-8 at the DISC leads to the induction of DR-mediated apoptosis. The activation of procaspase-8 is blocked by cellular FLICE-inhibitory proteins (c-FLIP). This review is focused on the role in the CD95-mediated signaling of the death effector domain-containing proteins procaspase-8 and c-FLIP. We discuss how dynamic cross-talk between procaspase-8 and c-FLIP at the DISC regulates life/death decisions at CD95.

Figure 1

The CD95 DISC and complex II. The DISC consists of CD95, (depicted in yellow), FADD, (depicted in light blue), procaspase-8/procaspase-10, (depicted in green) and c-FLIP (depicted in violet). Complex II comprises FADD, procaspase-8/10 and c-FLIP. DD are shown in red; DED are shown in light yellow. The interactions between the molecules at the DISC and complex II are based on homotypic contacts. The DD of CD95 interacts with the DD of FADD while the DED of FADD interacts with the N-terminal tandem DEDs of procaspase-8, procaspase-10 and c-FLIP. The color reproduction of this figure is available at the Cell Death and Differentiation journal online

Figure 2

Scheme of procaspase-8 and the two-step mechanism of procaspase-8 activation. Procaspase-8a/b (p55/p53) is shown in green; DEDs are presented in light yellow. The N-terminal cleavage products: p43/p41, prodomains p26/p24, CAP3; C-terminal cleavage product p30 as well as caspase-active domains p18 and p10 are indicated. Two cleavage steps with the resulting products are presented. The color reproduction of this figure is available at the Cell Death and Differentiation journal online

Figure 3

The scheme of c-FLIP proteins. c-FLIP isoforms and c-FLIP cleavage products are shown. DEDs and caspase-like domains (p20 and p12) are indicated. D376 and D196 leading to the generation of p43-FLIP and p22-FLIP, respectively, are presented in red. The color reproduction of this figure is available at the Cell Death and Differentiation journal online

Figure 4

DED proteins: procaspase-8 and c-FLIP at the DISC and in the cytosol. Upon CD95 stimulation the CD95 DISC is formed. Cleavage products of procaspase-8 and c-FLIP_L, p43/p41 and p43-FLIP, respectively, are generated at the DISC. p43/p41 leads to the induction of apoptosis, while p43-FLIP binds to the IKK complex, which results in the induction of NF-κB. Procaspase-8 and c-FLIP form dimers producing p22-FLIP. p22-FLIP binds to the IKK complex via IKKγ, which leads to the induction of NF-κB. The color reproduction of this figure is available at the Cell Death and Differentiation journal online