Fas/CD95 Signaling Pathway in Damage-Associated Molecular Pattern (DAMP)-Sensing Receptors

Abstract

Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its natural ligand, CD95L, and the cellular distribution where these PPIs take place render it difficult to predict what will be the cellular outcome associated with the receptor engagement. Accordingly, CD95 stimulation can trigger apoptosis, necroptosis, pyroptosis, or pro-inflammatory signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphatidylinositol-3-kinase (PI3K). Recent data suggest that CD95 can also activate pattern recognition receptors (PRRs) known to sense damage-associated molecular patterns (DAMPs) such as DNA debris and dead cells. This activation might contribute to the pro-inflammatory role of CD95 and favor cancer development or severity of chronic inflammatory and auto-immune disorders. Herein, we discuss some of the molecular links that might connect the CD95 signaling to DAMP sensors.

Keywords: CD95; apoptosis; auto-immunity; inflammasome; necroptosis; pyroptosis; sting.

Figure 1

CD95 stimulation and potential links with inflammasome activation. At least three molecular complexes could occur upon CD95 engagement to trigger either apoptosis (pink circle), inflammation (green circle), or necrosis (blue circle). Apoptotic and necroptotic complexes control each other and the inflammatory complex (red lines). Necroptosis and pyroptosis signaling pathways lead to the break of the plasma membrane. IAPs also control an additional complex and these members are known to participate in the TNF-R-mediated signaling pathway. The NLRP3 inflammasome, which is activated by signal 1 + 2 is depicted. (GsdmD = Gasdermin D).

Figure 2

Representation of ion channels involved in the inflammasome activation. Different plasma membrane or endoplasmic reticulum ion channels have been involved in ion fluxes (black arrows) responsible for the signal 2 activating the inflammasome.