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Review
. 2024 Nov 3;13(21):1814.
doi: 10.3390/cells13211814.

The Crosstalk of Apoptotic and Non-Apoptotic Signaling in CD95 System

Kamil Seyrek  1 , Johannes Espe  1 , Elisabeth Reiss  1 , Inna N Lavrik  1
Affiliations
Review

The Crosstalk of Apoptotic and Non-Apoptotic Signaling in CD95 System

Kamil Seyrek et al. Cells. .

Abstract

The mechanisms of CD95 (Fas/APO-1)-mediated extrinsic apoptotic pathway in cancer cells have been extensively studied. The majority of human cells express CD95, but not all these cells can induce extrinsic apoptosis. Accumulating evidence has shown that CD95 is a multifunctional protein, and its stimulation can also elicit non-apoptotic or even survival signals. It has become clear that under certain cellular contexts, due to the various checkpoints, CD95 activation can trigger both apoptotic and non-apoptotic signals. The crosstalk of death and survival signals may occur at different levels of signal transduction. The strength of the CD95 stimulation, initial levels of anti-apoptotic proteins, and posttranslational modifications of the core DISC components have been proposed to be the most important factors in the life/death decisions at CD95. Successful therapeutic targeting of CD95 signaling pathways will require a better understanding of the crosstalk between CD95-induced apoptotic and cell survival pathways. In this review, in order to gain a systematic understanding of the crosstalk between CD95-mediated apoptosis and non-apoptotic signaling, we will discuss these issues in a step-by-step way.

Keywords: CD95; DISC; caspase; extrinsic apoptosis; non-apoptotic signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Scheme of CD95 pathway. The CD95 signaling pathway is of crucial importance for the homeostasis of multicellular organisms. Binding of CD95L to the CD95 initiates the signaling pathway and leads to assembly of the death-inducing signaling complex (DISC). Ligand binding results in a conformational change of the intracellular death domain (DD), which leads to the recruitment of FADD via its DD. FADD comprises a death effector domain (DED) through which it recruits other DED-containing DISC core proteins that form the DED filaments. These DED proteins include procaspase-8 and the c-FLIP isoforms. While c-FLIPShort acts exclusively antiapoptotic, c-FLIPLong can act both proapoptotic and antiapoptotic. At the DISC, procaspase-8 can be activated both as a homodimer and as a procaspase-8/c-FLIPLong heterodimer and is cleaved to the heterotetrameric caspase-8. In type I cells, caspase-8 activation is sufficient to activate the effector caspases procaspase-3 and -7 and thus trigger apoptosis. In type II cells, amplification of the signal is necessary. In this case, caspase-8 cleaves BID to tBID, which in turn leads to permeabilization of the mitochondrial membrane and the release of cytochrome c. Cytochrome c, together with cytosolic APAF1 and procaspase-9, forms the apoptosome, which serves as a platform for caspase-9 activation. Caspase-9 activates the effector caspases and triggers apoptosis in type II cells. XIAP is an inhibitor of caspase-9 and the effector caspases. Through various stress signals, BAX and BAK are also able to permeabilize the mitochondrial membrane and trigger apoptosis in a CD95-independent manner. BCL-2 can inhibit BAX/BAK-mediated permeabilization. Figure created using BioRender.com, accessed on 26 September 2024.
Figure 2
Figure 2
The scheme of CD95-mediated apoptotic and non-apoptotic signaling. Various factors contributing to the induction of apoptotic versus non-apoptotic NF-κB pathways are shown. CD95 stimulation leads to the formation of the DISC and the FADDosome, the latter consisting of FADD, RIPK1, c-FLIP, and caspases -8 and -10. Both the DISC and the FADDosome can have proapoptotic as well as antiapoptotic effects. DED proteins interact with NEMO, a part of the IKK complex. The interaction with NEMO results in the activation of IKK complex, subsequent ubiquitin-mediated proteasomal degradation of IκBα, and translocation of p50 and p65 into the nucleus, where they activate NF-κB target genes. A20 can inhibit activation of the IKK complex. Figure created using BioRender.com, accessed on 26 September 2024.
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