FADD at the Crossroads between Cancer and Inflammation

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. 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. G protein-coupled receptors mediating the physiological actions of adenosine, and involved in many pathophysiological processes such as immune responses, inflammatory diseases, and cancer. atypical glycosylation of arginine residues mediated by bacterial glycosyltransferase enzymes not observed in eukaryotic cells. a form of regulated cell death that depends on the autophagic machinery. a gene whose amplification-driven overexpression would confer an advantage to cancer cells harboring the amplification. host molecules released following tissue damage and activating inflammatory response. anticancer drug inhibiting topoisomerase II, which leads to DNA strands break and apoptosis of cancer cells. serine protease constitutively and abundantly expressed in NK cells that cleaves its substrate preferentially after a leucine, methionine, or proline. reduced splenic functioning. complex formed by FADD and RIPK1 in response to the recognition of viral dsRNAs by an intracellular receptor in order to regulate TBK-1-mediated activation of IRF-3 and IFN-β production. macrophages polarized towards an anti-inflammatory phenotype thus deemed to harbor immunosuppressive and tumor-promoting functions. plasma-membrane-derived extracellular vesicles (100–1000 nm) released from various cells, exposing phosphatidylserines and adhesion molecules, and containing miRNAs and proteins such as signaling molecules, chaperones, or biogenesis factors. noncoding ssRNAs usually 22 nucleotides long that can regulate gene expression. microfilament-like complex formed by RIPK1 and RIPK3 leading to activation of the MLKL kinase and subsequent necroptosis. a cytosolic multiprotein complex composed of the sensor NLRP3, the adaptor ASC and pro-caspase-1, which assembles following detection of pathogen or danger signals, and ultimately leads to the secretion of pro-inflammatory cytokines such as IL-1β, and pyroptosis, an inflammatory form of cell death. activated by Gram-negative bacteria and require caspase-4/5 (humans) or -11 (mice) for subsequent canonical activation. anticancer drug that binds and stabilizes microtubules, leading to cell cycle arrest and apoptosis of the cells. microbial molecules detected by pattern recognition receptors and activating inflammatory response. serine/threonine kinase family that can transduce inflammatory and cell death signals. a fatty liver disease characterized by chronic liver inflammation. reversible transfer of a SUMO protein on a lysine residue of the target protein through the action of one conjugating-enzyme UBC9. class of receptors sensing PAMPs and DAMPs and activating the innate immune system. reversible covalent conjugation of an ubiquitin (70 amino acids protein) on one or many lysine residues of a protein by the action of an E3 ubiquitin ligase. Ubiquitinated proteins are often addressed to the proteasome for degradation.