Trends in Immunology
Volume 39, Issue 12, December 2018, Pages 1036-1053
Journal home page for Trends in Immunology

Review
FADD at the Crossroads between Cancer and Inflammation

https://doi.org/10.1016/j.it.2018.10.005Get rights and content

Highlights

FADD is part of most signalosome complexes including the necroptosome, FADDosome, innateosome and inflammasome.

Human FADD gene can be a potential driver in cancer through its amplification, which has been associated with both metastasis and poor overall survival for certain malignancies.

FADD has been implicated in immune defenses against bacterial and viral infections, and a human FADD missense mutation has led to severe and potentially lethal, infectious diseases.

FADD activity can be modulated by several post-translational modifications (phosphorylation, SUMOylation, ubiquitination, cleavage, and arginine GlcNAcylation) as well as via its cellular localization (nuclear/cytoplasmic/extracellular).

FADD might play a critical role in cancer, innate immunity, and inflammation. The role of FADD in tumoral and inflammatory responses may be dual, with FADD exerting either anti- or protumoral/inflammatory effects, depending the cell type and model.

Initially described as an adaptor molecule for death receptor (DR)-mediated apoptosis, Fas-associated death domain (FADD) was later implicated in nonapoptotic cellular processes. During the last decade, FADD has been shown to participate and regulate most of the signalosome complexes, including necrosome, FADDosome, innateosome, and inflammasome. Given the role of these signaling complexes, FADD has emerged as a new actor in innate immunity, inflammation, and cancer development. Concomitant to these new roles, a surprising number of mechanisms deemed to regulate FADD functions have been identified, including post-translational modifications of FADD protein and FADD secretion. This review focuses on recent knowledge of the biological roles of FADD, a pleiotropic molecule having multiple partners, and its impact in cancer, innate immunity, and inflammation.

Section snippets

FADD: Roles beyond Apoptosis

FADD is a nearly ubiquitous, well conserved across species, key adaptor protein transmitting apoptotic signals mediated by the DRs of the tumor necrosis factor (TNF) receptor (TNF-R) superfamily such as TNF-R1, FAS (CD95/APO-1), DR3, TRAIL (TNF-related apoptosis-inducing ligand)-R1 (DR4) and TRAIL-R2 (DR5) 1, 2, 3, 4. In all cell types, FADD can act as a bridge between these DRs and initiator pro-caspase-8/10, mediated by two highly conserved domains: the death domain (DD) and the death

FADDosome

Inflammation is a hallmark of numerous types of cancer, and many studies have highlighted a clear role for FADD in inflammation. A recent report described a FADDosome complex involved in regulating inflammation upon TRAIL stimulation [23]. Although engagement of TRAIL-R1 or -R2 by TRAIL could induce apoptosis through FADD recruitment and caspase-8 activation [4] (Figure 1A), it is suggested that TRAIL-R stimulation could also lead to nuclear factor (NF)-κB activation in human cell lines [23].

FADD: Putative Cancer Driver

Human FADD gene is located on chromosome 11q13.3, a region prone to amplification in several human malignancies including breast, lung, skin, esophagus, and head and neck cancers [48]. These amplification events have prompted the idea that an abnormal FADD gene might act as a potential cancer driver [48]. However, FADD gene amplification seems to be cancer-type specific as it is not found in human lung adenocarcinoma [49] but is reported in oral, esophageal, laryngeal, and breast carcinomas,

Regulation of FADD Protein by Phosphorylation: Implications in Cancer

Human FADD protein can be phosphorylated at serine 194 [15], 200 [55], and 203 [56] (Figure 3A), and several kinases/phosphatases regulating FADD phosphorylation have been described (Figure 3B and Box 2). FADD phosphorylation at Ser194, or at its homolog Ser191 in mice [16], is cell-cycle dependent and necessary for the G2/M transition, and therefore cell proliferation 15, 17, 57. This phosphorylation site also regulates FADD subcellular localization: Ser194 phosphorylated FADD (194P-FADD) is

Concluding Remarks

Collectively, these studies suggest that FADD plays a role in tumorigenesis, given that FADD gene overexpression is associated with tumor growth and poor prognosis in certain cancer patients 60, 61, 62. Nonetheless, FADD might also promote tumor suppression via its proapoptotic function [23]. The opposing roles of FADD in tumor development might be related to the opposing functions of FADD in inflammatory processes. Indeed, FADD is a key signaling molecule implicated in most signalosome

Glossary

Adenosine receptors
G protein-coupled receptors mediating the physiological actions of adenosine, and involved in many pathophysiological processes such as immune responses, inflammatory diseases, and cancer.
Arginine GlcNAcylation
atypical glycosylation of arginine residues mediated by bacterial glycosyltransferase enzymes not observed in eukaryotic cells.
Autophagic cell death
a form of regulated cell death that depends on the autophagic machinery.
Cancer driver
a gene whose amplification-driven

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