The Many Roles of FAS Receptor Signaling in the Immune System

Abstract

Summary FAS (also known as APO-1 or CD95) belongs to the subgroup of the tumor necrosis factor receptor (TNF-R) family that contain an intra-cellular ‘death domain’ and can trigger apoptosis. Its physiological ligand, FASL (CD95L), is a member of the corresponding TNF cytokine family. Studies with spontaneous mutant mice, gene-targeted mice and cells from human patients have shown that FAS and FASL play critical roles in the immune system, in particular in the killing of pathogen infected target cells and the death of no longer needed, potentially deleterious as well as autoreactive lymphocytes. This ligand-receptor pair thereby functions as a guardian against autoimmunity and tumor development. FASL-FAS signaling triggers apoptosis through FADD (Fas-associated protein with death domain, also called MORT1) adaptor protein-mediated recruitment and activation of the aspartate-specific cysteine protease, caspase-8. In certain cells such as hepatocytes, albeit not in lymphocytes, FAS-induced apoptosis signaling requires amplification through proteolytic activation of the pro-apoptotic BCL-2 family member BID. Curiously, several components of the FAS signaling machinery have been implicated in non-apoptotic processes, including cellular activation, differentiation and proliferation. Here we describe current knowledge of the roles of FASL and FAS in the immune system, discuss important unresolved issues and propose experimental approaches to address them.

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Furthermore, in response to pathogen infection, caspase-8 is involved in the processing of pro-IL-1b/ IL-18 to yield active cytokines in an inflammasome-independent manner (Latz et al 2013). In contrast to caspase-1, caspase-8 is activated by dectin-1, TLRs, and Fas located on the plasma membrane (Gringhuis et al 2012;Lemmers et al 2007;Strasser et al 2009). Recently, Fas-activated caspase-8 has been shown to contribute to the production of inflammatory cytokines and the host defense towards pathogenic bacterial infections (Uchiyama et al 2013).…”

“…Caspase-8 is a well-described protease that induces apoptosis following stimulation with Fas or TNF-a signaling (Strasser et al 2009). Here, we provide a brief summary of caspase-8 activation with an example of the Fas ligand (FasL)-Fas signaling pathway.…”

“…In the context of the host defense system, it has been shown that Fas signaling contributes to the apoptotic elimination of virus-infected or tumor cells (Strasser et al 2009). In addition, Fas signaling contributes to the production of active IL-1b/IL-18; injection of FasL-expressing cells into the peritoneal cavity of mice induces the production of active IL-1b and the accumulation of neutrophils (Miwa et al 1998).…”

Flow cytometric analyses disclose intercellular communications in FasL‐stimulated T cells: Results and trouble shooting

“…At least in some cell types, FasL can be stored in granules and then rapidly released at the cell surface in response to external stimuli. Alternatively, FasL can be cleaved from the membrane by matrix metalloproteases and act as a soluble cytokine (6). In its membrane-bound form, FasL acts as a ligand for Fas and can trigger Fas-induced death.…”

Ezrin is a negative regulator of death receptor-induced apoptosis

“…Fas (CD95)-induced cell death starts from formation of sodium dodecyl sulfate-resistant Fas microaggregates, followed by the formation of death-inducing signaling complexes (DISCs) containing Fas-associated protein with death domain (FADD), procaspase-8 and cellular-FLICE inhibitory protein (c-FLIP) (Nagata, 1997;Algeciras-Schimnich et al, 2002;Peter and Krammer, 2003;Peter et al, 2007;Strasser et al, 2009). The processing of pro-caspase-8 to caspase-8 in DISC leads to the activation of effector caspases and eventual cell death.…”