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FADD

Fas-associated death domain protein (FADD) is an adaptor protein encoded by the FADD gene located on chromosome 11q13.3 in humans, playing a central role in transducing extrinsic apoptotic signals from death receptors such as Fas (CD95), TNFR1, DR4, and DR5.^[1] It facilitates the assembly of the death-inducing signaling complex (DISC) by recruiting and activating initiator caspases like caspase-8 and caspase-10 through its death effector domain (DED), thereby initiating the caspase cascade that leads to programmed cell death.^[2] FADD contains two key structural domains: a C-terminal death domain (DD) that interacts with the DD of death receptors or adaptor proteins like TRADD, and an N-terminal DED that binds to the DEDs of procaspases, enabling signal propagation.^[3] Beyond apoptosis, FADD regulates non-apoptotic processes including cell cycle progression by modulating the APC/C-Cdh1 ubiquitin ligase, innate immune responses, T-cell activation, and autophagy, highlighting its pleiotropic functions in cellular homeostasis.^[1]^[4] Dysregulation of FADD is implicated in various pathologies; for instance, germline mutations cause FADD-related immunodeficiency, characterized by recurrent infections and impaired T- and B-cell function due to disrupted signaling.^[1] In cancer, FADD amplification or overexpression in tumors such as breast cancer, head and neck squamous cell carcinoma (HNSCC), and oral squamous cell carcinoma (OSCC)—with amplification rates of 13-44% in OSCC—promotes apoptosis resistance, metastasis, and poor prognosis by altering death receptor signaling.^[2] Conversely, FADD deficiency can lead to embryonic lethality or autoinflammatory disorders in animal models, underscoring its essential role in balancing life and death decisions.^[4] FADD is ubiquitously expressed across human tissues, with highest levels in the kidney and colon, and its activity is tightly regulated by phosphorylation, ubiquitination (e.g., via MKRN1), and interactions with proteins like RIPK1 to prevent aberrant necroptosis or NF-κB activation.^[1]^[5] Recent structural studies using cryo-EM have revealed the dynamic architecture of FADD:caspase-8 complexes, which determines whether cells undergo apoptosis or survival signaling based on complex composition and plasticity.^[6]

Introduction

Discovery and Nomenclature

The protein now known as Fas-associated death domain (FADD), also called mediator of receptor-induced toxicity 1 (MORT1), was first identified in 1995 through a yeast two-hybrid screen of a HeLa cell cDNA library, where it was cloned as a novel interacting partner specifically binding to the death domain of the Fas receptor (also known as APO-1 or CD95), a key mediator of apoptosis.^[7] This discovery, reported by Boldin et al., highlighted the protein's role in Fas-mediated cell death signaling, as its induced expression triggered ligand-independent cytotoxicity, and it contained a conserved death domain motif similar to that in Fas, enabling homotypic interactions. The protein was named MORT1 in this study. Independently in the same year, the protein was cloned and characterized by another group using a similar yeast two-hybrid approach with the Fas intracellular domain as bait, leading to its formal naming as Fas-Associated protein with Death Domain (FADD).^[8] This nomenclature reflected its specific association with the Fas death domain and its possession of a homologous death domain, which facilitated direct binding to Fas and the initiation of apoptotic signaling upon overexpression. The Chinnaiyan et al. study confirmed that FADD is identical to MORT1. Both names have persisted in the literature, with FADD becoming the more commonly used designation in reference to its structural and functional features. Early investigations in the mid-1990s extended FADD's role beyond Fas to signaling by other members of the tumor necrosis factor (TNF) receptor family, particularly through its recruitment to the TNF receptor 1 (TNFR1) via the adaptor protein TRADD, thereby linking it to TNF-induced cell death pathways.^[9]

Gene and Expression

The human FADD gene is located on chromosome 11q13.3 and spans approximately 3.6 kb, consisting of two exons separated by a 2-kb intron.^[10]^[11] The gene encodes a protein of 208 amino acids with a calculated molecular weight of approximately 23 kDa.^[3]^[1] FADD is ubiquitously expressed across human tissues, with the highest levels observed in the spleen and peripheral blood leukocytes, reflecting its prominence in immune cells such as T cells.^[12] Expression is regulated by promoters that respond to cellular stress signals, enabling adaptive modulation in response to environmental cues.^[13] In humans, no major splice variants of FADD have been identified, with only one primary isoform produced; however, post-translational modifications such as phosphorylation generate functional variants that influence protein activity.^[1]^[14]^[15] The FADD gene exhibits strong evolutionary conservation across vertebrates, with orthologs present in mammals, birds, reptiles, and fish; in invertebrates, homologs such as dFADD in Drosophila melanogaster perform analogous adaptor functions in immune and death signaling pathways.^[3]^[16]^[17]

Molecular Structure

Protein Domains

FADD is a soluble cytoplasmic adaptor protein comprising 208 amino acids in humans, lacking any transmembrane region and thus functioning without membrane anchoring. Its domain architecture consists of two principal interaction modules: an N-terminal death effector domain (DED) and a C-terminal death domain (DD), which together enable FADD to bridge death receptors and initiator caspases in signaling cascades.^[18] The DED, spanning residues 1–80, forms a compact α-helical bundle structure characterized by six antiparallel amphipathic α-helices connected by short loops. This fold, conserved among DED-containing proteins, facilitates homotypic interactions critical for downstream effector recruitment. The solution NMR structure of a biologically active mutant of the human FADD DED (F25Y variant) reveals this helical arrangement, highlighting a hydrophobic core stabilized by residues such as Phe25 (or the mutant Tyr25) that contribute to overall domain stability and solubility.^[19] The DD, encompassing residues 81–208 (approximately 128 residues), exhibits a Greek key-like topology also composed of six α-helices, homologous to DDs in tumor necrosis factor receptor family members like Fas/CD95. This domain mediates homotypic death domain associations through charged surfaces, particularly involving helices α2 and α3, which form electrostatic interfaces in complex assemblies. The solution NMR structure of the human FADD DD (PDB: 1E3Y) demonstrates this compact, up-and-down helical bundle, with overall similarity to the Fas DD, underscoring its role in adaptor-receptor docking.^[20] For comparative insight, the murine FADD DD structure (PDB: 1FAD) confirms the conserved fold, with residues 89–183 aligning closely to the human sequence in secondary structure and key interaction motifs.^[21]^[22] These domains adopt an orthogonal, tail-to-tail orientation in the full-length FADD structure, positioning the DED for effector binding while the DD engages receptor tails, without evidence of intrinsic disorder or additional modular elements.

Conformational Changes and Oligomerization

Upon binding of Fas ligand (FasL) to the Fas receptor, a conformational shift occurs in the Fas death domain (DD), transitioning from a closed, autoinhibited state to an open conformation that exposes the binding site for the FADD DD.^[23] This "on switch" mechanism, recently modeled using AlphaFold-Multimer in 2025, involves a rearrangement from anti-parallel non-signaling dimers to parallel signaling dimers, unmasking key residues and facilitating receptor clustering.^[24] In the death-induced signaling complex (DISC), the exposed Fas DD interfaces recruit FADD DDs through homotypic death domain interactions, leading to oligomerization. Cryo-EM structures from 2025 reveal that this assembly forms an asymmetric 7:5 oligomer consisting of seven Fas DDs and five FADD DDs, organized in a three-layered architecture that stabilizes the complex and promotes downstream signaling.^[25] These interfaces involve specific hydrophobic and charged contacts, enabling the tight packing observed at 3.51 Å resolution. Beyond the DD-mediated oligomer, the N-terminal death effector domain (DED) of FADD undergoes concentration-dependent oligomerization into helical filaments upon activation. These FADD DED filaments adopt a hollow helical structure with C3 symmetry, an outer diameter of 90 Å, a central cavity of 20 Å, an axial rise of approximately 14 Å, and a helical twist of 49°, stabilized by Type I, II, and III interfaces.^[25] Recent cryo-EM advances in 2025 have elucidated the role of FADD DED filaments in complex IIa assembly during TNF signaling, where they form three intertwined helical chains via iterative interactions involving a unique serine-rich motif.^[26] This filamentation nucleates caspase-8 tandem DED polymerization and recruits RIPK1, with molecular dynamics simulations confirming thermodynamic favorability for ordered assembly; disruption of these filaments via mutagenesis abolishes apoptotic signaling.^[26]

Biological Functions

Role in Extrinsic Apoptosis

FADD serves as a critical adaptor protein in the extrinsic apoptosis pathway, facilitating signal transduction from death receptors to the caspase cascade. Upon ligand binding to death receptors such as Fas (CD95), FADD is recruited to the intracellular death domain (DD) of the receptor through homotypic interactions between its own DD and the receptor's DD. This recruitment initiates the formation of the death-inducing signaling complex (DISC), where FADD's death effector domain (DED) then binds to the DED of procaspase-8 (also known as FLICE), thereby bridging the receptor to the initiator caspase.^[27] The assembly of the DISC promotes the oligomerization and proximity-induced auto-activation of procaspase-8, leading to its cleavage into active caspase-8. Active caspase-8 then proteolytically activates downstream effector caspases, such as caspase-3, initiating the apoptotic cascade that culminates in cell death. This process occurs efficiently in type I cells, where high levels of DISC formation generate sufficient active caspase-8 to directly activate effector caspases without mitochondrial involvement; in type II cells, lower DISC activity requires amplification through the mitochondrial pathway via Bid cleavage. FADD's role in this activation is essential, as dominant-negative mutants of FADD block caspase-8 recruitment and apoptosis induction.^[27] FADD mediates extrinsic apoptosis downstream of multiple death receptors, including Fas/CD95, tumor necrosis factor receptor 1 (TNFR1), death receptor 3 (DR3), and the TRAIL receptors DR4 and DR5. For Fas and DR4/DR5, FADD directly binds the receptor DDs to form the DISC. In contrast, for TNFR1 and DR3, FADD is indirectly recruited via the adaptor TRADD, which first interacts with the receptor before engaging FADD to propagate the death signal. This versatility underscores FADD's central position in death receptor signaling.^[9]^[28]^[29] Experimental evidence from FADD-deficient models confirms its indispensable role in extrinsic apoptosis. Chimeric mice generated from FADD-null embryonic stem cells exhibit defective Fas-mediated apoptosis in lymphocytes, with mature T cells showing profound resistance to anti-Fas antibody-induced cell death. Similarly, these cells fail to undergo activation-induced cell death upon TCR stimulation combined with IL-2, highlighting FADD's necessity for lymphocyte homeostasis through extrinsic apoptotic pathways.

Involvement in Necroptosis

FADD plays a critical role in regulating necroptosis, a form of programmed necrotic cell death that occurs when apoptotic signaling is compromised, such as through caspase inhibition. In this context, FADD participates in the assembly of the ripoptosome, a multiprotein complex comprising receptor-interacting protein kinase 1 (RIPK1), FADD itself, and caspase-8, which forms in response to stimuli like tumor necrosis factor (TNF) signaling or genotoxic stress. Under normal conditions, FADD bridges RIPK1 to caspase-8 via death domain (DD) interactions, promoting caspase-8 activation and subsequent cleavage of RIPK1 and RIPK3 to favor apoptosis and suppress necroptosis. However, when caspases are inhibited—e.g., by pharmacological agents like zVAD-fmk—FADD's scaffolding function in the ripoptosome facilitates the recruitment and activation of RIPK3 through RIPK1's RIP homotypic interaction motif (RHIM), shifting the complex toward necrosome formation (RIPK1-RIPK3). The necrosome then phosphorylates mixed lineage kinase domain-like (MLKL), leading to MLKL oligomerization, membrane permeabilization, and necroptotic cell lysis.^[30]^[31]^[32] This pathway divergence is particularly evident in response to TNF or viral infections combined with caspase inhibition, where FADD's interactions enable RIPK1 ubiquitination to be curtailed, preventing prosurvival NF-κB signaling and promoting RIPK3-MLKL activation. For instance, in TNF-stimulated cells treated with zVAD-fmk, FADD deficiency disrupts ripoptosome integrity but paradoxically sensitizes cells to necroptosis in certain contexts by removing the apoptotic checkpoint. Viral infections, such as those inducing interferon signaling, can similarly trigger necroptosis via FADD-containing complexes when caspases are blocked, highlighting FADD's dual role in pathway selection.^[33]^[34]^[35] In vivo evidence underscores FADD's protective function against excessive necroptosis. Epidermal keratinocyte-specific deletion of FADD in mice leads to RIPK3-dependent necroptosis, resulting in severe inflammatory skin lesions characterized by hyperproliferation, immune cell infiltration, and barrier dysfunction. This phenotype is rescued by concomitant RIPK3 knockout, confirming necroptosis as the driver. Recent studies have linked these mechanisms to innate immune sensors; for example, STING-ZBP1 signaling can induce RIPK3-mediated necroptosis in keratinocytes independently of TNFR1 and FADD, but FADD's absence exacerbates inflammation in caspase-8-deficient models, integrating necroptosis with autoinflammatory diseases like skin disorders. These findings illustrate FADD's essential role in balancing cell death modalities to maintain tissue homeostasis.^[36]^[37]^[38]

Participation in Other Cell Death Pathways

FADD participates in pyroptosis, a lytic form of programmed cell death characterized by gasdermin-mediated pore formation and inflammation. In ovarian cancer cells undergoing prolonged mitotic arrest, phosphorylated IRF3 recruits the RIPK1/FADD/caspase-8 complex to promote GSDME-dependent pyroptosis, highlighting FADD's role in linking mitotic stress to inflammatory cell death.^[39] Beyond pyroptosis, FADD contributes to autophagic cell death, where excessive autophagy leads to lysosomal degradation and cell demise. FADD interacts with Atg5, an essential autophagy protein, to form a complex that drives autophagic vacuole formation and subsequent cell death in response to cellular stress. Under endoplasmic reticulum (ER) stress, particularly in cells deficient in mitochondrial apoptosis pathways, FADD assembles with Atg5 and caspase-8 into a death-inducing complex on autophagosome membranes, amplifying autophagic signaling toward lethality.^[40]^[41] FADD also integrates into PANoptosis, a coordinated inflammatory cell death pathway combining features of pyroptosis, apoptosis, and necroptosis. In STING-activated scenarios, ZBP1 senses nucleic acids to form a PAN-optosome with RIPK1, RIPK3, and caspase-8 independent of FADD, driving multifaceted cell death and cytokine release during viral infections like HSV-1 in retinal cells. Although certain STING-ZBP1-driven necroptotic responses can proceed independently of FADD in specific contexts, FADD generally modulates ZBP1 activity by suppressing spontaneous activation, ensuring regulated PANoptotic outcomes.^[38]^[42] The involvement of FADD in these diverse death pathways is evolutionarily conserved, as evidenced by invertebrate homologs. In the beetle Tenebrio molitor, TmFADD, the ortholog of mammalian FADD, participates in immune defense against bacterial and fungal pathogens by facilitating IMD pathway signaling, which induces antimicrobial responses and potentially immune-related cell death, underscoring FADD's ancient role in stress-induced lethality.^[43]

Non-Death Functions

FADD plays a critical role in embryonic development, independent of its apoptotic functions. FADD-deficient mice exhibit embryonic lethality around day 11.5 of gestation, characterized by heart defects such as cardiac failure and abdominal hemorrhage, highlighting FADD's necessity for proper cardiac morphogenesis.^[44] This lethality can be rescued by concomitant deletion of RIPK3, indicating that FADD suppresses necroptotic signaling during embryogenesis.^[45] In lymphocyte development, FADD is essential for T cell maturation in the thymus. Expression of a dominant-negative FADD mutant impairs early thymocyte development, leading to a block at the double-negative stage and absence of peripheral T cells, underscoring FADD's involvement in pre-T cell receptor signaling and positive selection.^[46] Similarly, FADD contributes to B cell maturation and homeostasis; conditional deletion in B cells results in altered splenic B cell numbers and reduced peritoneal B1 cells, though bone marrow development is largely unaffected.^[47] FADD regulates cell cycle progression through post-translational modifications. Phosphorylation of FADD at serine 194 by casein kinase 1α (CK1α) promotes the G1/S phase transition by enhancing nuclear localization and association with cell cycle regulators, including upregulation of cyclin D1 expression in T cells.^[48] This modification is cell cycle-dependent, peaking during G2/M, and its disruption impairs mitogen-induced proliferation in splenocytes.^[48] FADD supports lymphocyte proliferation beyond development, particularly in T cells responding to costimulatory signals. In peripheral T cells, FADD facilitates initial proliferation following T cell receptor stimulation by promoting NF-κB activation, which drives expression of survival and growth genes; FADD deficiency leads to defective clonal expansion upon antigen or mitogen challenge. This NF-κB-dependent pathway complements Bcl-3-mediated sustained proliferation, ensuring robust T cell responses. In innate immune regulation, FADD participates in Toll-like receptor (TLR) signaling, including recruitment to the TLR3-TRIF complex to mediate cell death pathways such as apoptosis, while exhibiting inhibitory effects on proinflammatory cytokine production in response to TLR3 agonists in certain cell types.^[49]^[50]

Regulation

Subcellular Localization

Under resting conditions, Fas-associated death domain (FADD) protein is primarily soluble and localized in the cytosol, where it remains inactive until stimulated by external signals.^[51] This cytoplasmic distribution positions FADD as a readily available adaptor for rapid signaling responses, consistent with its role as a key mediator in death receptor pathways.^[52] Upon ligation of death receptors such as Fas (CD95), FADD rapidly translocates from the cytosol to the plasma membrane, where it is recruited to the death-inducing signaling complex (DISC) through homotypic interactions between its death domain (DD) and the receptor's intracellular DD.^[52] This recruitment is highly specific and dependent on the structural integrity of the DD, enabling FADD to bridge the receptor with downstream effectors.^[51] Live-cell imaging studies using fluorescently tagged FADD and Fas have demonstrated that this translocation and DISC assembly occur dynamically, initiating within 8–15 minutes post-ligation and peaking around 60 minutes, highlighting the spatiotemporal precision of the process.^[53] In addition to its predominant cytosolic and membrane-associated pools, a minor fraction of FADD localizes to the nucleus, facilitated by a nuclear localization signal within its death effector domain.^[51] Nuclear FADD has been implicated in modulating cell cycle gene regulation, with phosphorylated forms accumulating in the nucleus during interphase to influence progression through the cell cycle.^[54] This compartmentalization underscores FADD's versatile trafficking, though the nuclear pool constitutes only a small proportion under basal conditions.^[51]

Regulatory Interactions and Modifications

One key regulatory mechanism of FADD activity involves inhibition by cellular FLICE-like inhibitory protein (c-FLIP), which competes with caspase-8 for binding to the death effector domain (DED) of FADD within the death-inducing signaling complex (DISC). This binding prevents caspase-8 recruitment and autoactivation, thereby suppressing extrinsic apoptosis and redirecting signaling toward pro-survival outcomes, such as NF-κB-mediated transcription.^[55] Isoforms of c-FLIP, including c-FLIP_L and c-FLIP_S, form heterodimers with caspase-8 via their DEDs, further stabilizing inhibitory complexes at the DISC and modulating the balance between cell death and survival signals.^[56] Post-translational phosphorylation significantly controls FADD function, with specific sites influencing distinct pathways. Phosphorylation at serine 194 (S194 in humans; equivalent to S191 in mice) by casein kinase 1α (CK1α) promotes FADD's nuclear translocation and non-apoptotic roles, including enhancement of cell proliferation through interactions with cell cycle regulators like cyclin B1.^[15] Conversely, in contexts of caspase inhibition, phosphorylation at the same site disables FADD's ability to suppress necroptosis by disrupting its interaction with RIPK1, thereby licensing RIPK1/RIP3-mediated necroptotic signaling during interferon-induced stress.^[34] Protein kinase C ζ (PKCζ) also phosphorylates FADD at serine 194, contributing to its nuclear localization and cell cycle regulation.^[57] These modifications can induce subtle shifts in FADD subcellular localization, favoring cytoplasmic retention or nuclear entry depending on the kinase context.^[58] Ubiquitination serves as another critical control point, with Makorin Ring Finger Protein 1 (MKRN1) acting as an E3 ubiquitin ligase that targets FADD for K48-linked polyubiquitination and subsequent proteasomal degradation. This process limits FADD accumulation at the DISC, reducing sensitivity to death receptor ligands and thereby constraining excessive inflammatory responses triggered by prolonged signaling.^[5] MKRN1-mediated degradation is particularly relevant in maintaining homeostasis, as its inhibition stabilizes FADD levels and heightens apoptotic potential.^[59] Recent studies have identified additional post-translational modifications, such as hypoxia-mediated SUMOylation of FADD, which exacerbates necroptosis in endothelial cells by promoting its incorporation into necroptotic complexes under hypoxic conditions.^[60] Recent structural models describe FADD, as a death fold domain (DFD) adaptor, participating in phase-separated condensates that function akin to biological batteries, storing and releasing signaling energy to coordinate innate immune decisions between apoptosis and other fates. These phase-change properties, observed in 2025 studies, enable efficient, privatized energy management in multiprotein assemblies during pathogen sensing.^[61]

Pathophysiological Roles

In Inflammatory Diseases

FADD plays a significant role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), where hyperphosphorylation of the protein at serine residues 191 and 194 facilitates its translocation to the nucleus of synovial fibroblasts. This nuclear accumulation enhances NF-κB transcriptional activity, leading to upregulated production of proinflammatory cytokines like IL-8 and matrix metalloproteinase-1 (MMP-1), which perpetuate joint inflammation and tissue destruction. In severe cases, this dysregulated cytokine release can contribute to storm-like inflammatory cascades, exacerbating synovial hyperplasia and immune cell infiltration characteristic of RA.^[62] In sepsis and septic shock, FADD modulates the TLR4/NF-κB signaling axis in immune cells, influencing the magnitude of TNF-α production in response to lipopolysaccharide (LPS). While FADD typically exerts a regulatory effect to prevent excessive activation, its involvement in death receptor complexes downstream of TNF can amplify inflammatory signaling when apoptosis is inhibited, promoting a feedback loop that sustains high TNF levels and systemic cytokine release during bacterial infection. This dynamic contributes to the hyperinflammatory state in sepsis, where unbalanced FADD function correlates with worsened organ dysfunction and mortality.^[50]^[63] FADD exerts a protective role against skin inflammation by inhibiting necroptosis in epidermal keratinocytes. Keratinocyte-specific FADD deficiency triggers RIPK3-dependent necroptosis, resulting in the release of damage-associated molecular patterns (DAMPs) that drive severe dermatitis-like lesions, characterized by hyperkeratosis, immune cell infiltration, and chronic inflammation. This mechanism highlights FADD's essential function in maintaining skin barrier integrity and preventing autoinflammatory dermatoses.^[36] Recent studies have elucidated FADD's involvement in the STING-ZBP1 axis during antiviral inflammation. Activation of the STING pathway by viral nucleic acids upregulates ZBP1 to form a multiprotein complex promoting PANoptosis—an integrated form of pyroptosis, apoptosis, and necroptosis—that enhances antiviral cytokine production and immune defense against pathogens like HSV-1. Dysregulation of this axis, particularly in contexts of caspase-8 or FADD deficiency, leads to uncontrolled necroptotic inflammation, underscoring its relevance to antiviral responses and potential autoinflammatory complications.^[38]^[42]

In Cancer

FADD exhibits dual roles in cancer, functioning both as a pro-carcinogenic factor through promotion of cell proliferation and survival in certain solid tumors, and as an anti-tumor mediator by facilitating apoptosis in response to death ligands like TRAIL. In head and neck squamous cell carcinoma (HNSCC), a 2025 study demonstrated that phosphorylated FADD at serine 194 drives tumor cell proliferation by activating the NF-κB pathway, leading to enhanced expression of pro-survival genes and perturbed cell cycle progression. This mechanism is particularly prominent in tumors with 11q13.3 amplification, where elevated nuclear FADD correlates with aggressive disease behavior. FADD overexpression has also been associated with tumor progression in ovarian cancer, contributing to chemoresistance.^[64] Conversely, FADD plays an anti-tumor role by sensitizing lymphoma cells to TRAIL-induced apoptosis, as it is essential for recruiting caspase-8 to the death-inducing signaling complex (DISC) upon TRAIL receptor activation. In Burkitt's lymphoma cell lines, adequate FADD expression enables efficient TRAIL-mediated caspase activation and cell death, whereas deficiencies impair this pathway and promote survival. FADD expression patterns vary across cancer types: it is frequently upregulated in breast and lung cancers due to genomic amplification at 11q13.3, fostering proliferation and metastasis, while low levels in acute myeloid leukemia correlate with resistance to extrinsic apoptosis pathways, including TRAIL, and poorer therapeutic responses.^[65]^[66]^[12] Elevated FADD levels serve as a prognostic marker in head and neck cancers, where high expression predicts poor overall survival and increased risk of lymph node metastasis, independent of other clinicopathological factors. In a cohort analysis, patients with FADD-overexpressing HNSCC tumors showed significantly shorter progression-free survival compared to those with low expression, highlighting its utility in risk stratification. These findings underscore FADD's context-dependent contributions to oncogenesis, influenced by its phosphorylation status and subcellular localization.^[67]^[68]^[69]

Therapeutic Targeting

Therapeutic strategies targeting FADD primarily focus on modulating its role in programmed cell death pathways to treat cancers and inflammatory disorders. In cancer therapy, TRAIL receptor agonists, such as recombinant human TRAIL (rhTRAIL) and agonistic antibodies against death receptors DR4 and DR5, activate the FADD-containing death-inducing signaling complex (DISC) to induce extrinsic apoptosis in tumor cells that are resistant to conventional treatments.^[66] These agents selectively trigger caspase-8 recruitment to FADD upon receptor ligation, bypassing resistance mechanisms like c-FLIP overexpression that compete for FADD binding.^[70] Clinical trials evaluating TRAIL agonists, including lexatumumab (anti-DR5) in phase II studies for non-Hodgkin lymphoma (NCT00497358) and dulanermin (rhTRAIL) combined with chemotherapy for non-small cell lung cancer (NCT00163042), have demonstrated tolerability and preliminary efficacy in overcoming apoptosis resistance, though broader adoption is limited by variable tumor responses.^[71] For inflammatory conditions driven by necroptosis, inhibitors of RIPK1 kinase, such as necrostatin-1 (Nec-1), prevent the formation of pro-necroptotic complexes involving FADD, thereby reducing excessive inflammation without broadly suppressing apoptosis.^[72] Nec-1 specifically blocks RIPK1 autophosphorylation, disrupting the ripoptosome assembly that includes FADD and caspase-8 under conditions of caspase inhibition, which has shown protective effects in preclinical models of sepsis and ischemia-reperfusion injury by limiting inflammatory cytokine release.^[73] This approach integrates FADD's involvement in necroptotic signaling to mitigate tissue damage in diseases like inflammatory bowel disease. In specific cancers, direct modulation of FADD has emerged as a targeted strategy. Similarly, in ovarian cancer, preclinical studies from 2025 have identified the phosphorylated IRF3-FADD interaction within the RIPK1/FADD/caspase-8 complex as a driver of GSDME-mediated pyroptosis during mitotic arrest, suggesting inhibitors targeting this interface could enhance pyroptotic cell death in chemotherapy-resistant cells.^[39] The dual functions of FADD in promoting both cell death and survival pathways pose significant challenges for therapeutic targeting, necessitating context-specific interventions to avoid unintended enhancement of inflammation or tumor progression.^[74] Ongoing efforts emphasize combination therapies, such as TRAIL agonists with SMAC mimetics, to fine-tune FADD-dependent signaling in clinical settings.^[75]

Protein Interactions

Death Receptor Signaling Complexes

FADD serves as a pivotal adaptor in the formation of the death-inducing signaling complex (DISC), primarily at the Fas (CD95) receptor. Ligand-induced trimerization of Fas exposes its intracellular death domain (DD), which recruits FADD via homotypic DD-DD interactions. The death effector domain (DED) of FADD then binds procaspase-8 and procaspase-10, forming a ternary DISC that promotes proximity-induced dimerization and autoproteolytic activation of these initiator caspases. This assembly has been confirmed through co-immunoprecipitation assays demonstrating stable Fas-FADD-caspase-8 associations upon Fas ligation. Structural analyses, including X-ray crystallography of the Fas DD-FADD DD complex, reveal an oligomeric interface that positions FADD DEDs for caspase recruitment. Recent cryo-EM studies further delineate the DISC's higher-order architecture as a helical assembly of FADD and caspase-8 DEDs, enabling signal amplification without requiring extensive receptor oligomerization.^[76]^[25] Beyond the DISC, FADD contributes to Complex II in tumor necrosis factor receptor 1 (TNFR1) signaling, a cytosolic platform that dictates apoptosis versus survival outcomes. Following TNFR1 stimulation, the initial membrane-bound Complex I (containing TRADD, RIPK1, and TRAF2) disassembles, releasing ubiquitinated RIPK1 to recruit FADD and caspase-8 through DD interactions. This Complex II also incorporates IKK for NF-κB activation and cFLIP to modulate caspase-8 activity; high cFLIP levels favor prosurvival signaling, while its absence promotes apoptosis. Co-IP experiments have isolated this RIPK1-FADD-caspase-8 core from TNF-treated cells, with RIPK1 ubiquitination preventing premature FADD recruitment in Complex I. A 2025 structural investigation using cryo-EM highlights FADD DED filaments in Complex II, showing how they scaffold caspase-8 heterodimers with cFLIP, thereby fine-tuning the apoptosis-survival switch.^[26] In response to genotoxic stress or inhibitor of apoptosis protein (IAP) depletion, FADD assembles the ripoptosome, a ~2 MDa cytosolic complex integrating death signals. This platform comprises RIPK1, FADD, RIPK3, caspase-8, and cFLIP isoforms, triggered by spontaneous DD associations independent of receptor ligation. Under stress, deubiquitination of RIPK1 enables its binding to FADD, recruiting RIPK3 for potential necroptosis or caspase-8 for apoptosis, with cFLIP levels biasing the outcome toward survival or cell death. Original co-IP studies identified the ripoptosome in etoposide-treated cells lacking cIAP1/2, confirming FADD's essential scaffolding role. Electron microscopy of the RIPK1 DD-FADD DD core depicts a compact helical structure that accommodates RIPK3 and caspase-8, underscoring FADD's versatility in stress-induced signaling.^[77]

Interactions with Kinases and Adaptors

FADD interacts with receptor-interacting serine/threonine kinase 1 (RIPK1) through homotypic death domain (DD) associations, forming part of the ripoptosome complex that regulates necroptosis and apoptosis.^[77] This DD-DD interaction is disrupted in RIPK1 mutants (e.g., R588E), leading to embryonic lethality due to unchecked necroptotic signaling.^[78] In necroptotic pathways, FADD-RIPK1 binding also modulates downstream RIPK3 activation, preventing excessive inflammation.^[79] Protein kinase C ζ (PKCζ) directly interacts with and phosphorylates FADD, thereby inhibiting its recruitment to death receptors and protecting cells from Fas-mediated apoptosis.^[80] PKC activation reduces FADD's affinity for the intracellular domains of TRAIL receptors, suppressing caspase activation.^[81] Casein kinase 1α (CK1α) phosphorylates FADD at serine 194 (S194), a modification essential for its non-apoptotic functions, such as cell cycle progression through G2/M phase.^[48] CK1α binds FADD in early mitosis, enhancing its stability and promoting proliferation independently of death signaling.^[82] Among adaptor proteins, tumor necrosis factor receptor-associated death domain (TRADD) recruits FADD in tumor necrosis factor receptor 1 (TNFR1) signaling, bridging TNFR1 to downstream caspase activation or NF-κB pathways.^[9] This TRADD-FADD interaction occurs via DD homotypy and is critical for TNFR1-induced apoptosis, distinct from direct Fas binding.^[83] Z-DNA-binding protein 1 (ZBP1) engages RIPK1 in STING-dependent necroptosis independently of FADD, forming a ZBP1-RIPK1-RIPK3 complex that can lead to perinatal lethality when dysregulated.^[84] Beclin-1 interacts weakly with FADD in autophagy regulation during cadmium-induced stress responses.^[85] Cellular FLICE-like inhibitory protein (c-FLIP) binds FADD via death effector domain (DED) interactions, forming inhibitory complexes that block caspase-8 activation in the death-inducing signaling complex (DISC).^[86] This DED-DED association allows c-FLIP to compete with procaspase-8, promoting survival signals over apoptosis.^[87] In pyroptosis, interferon regulatory factor 3 (IRF3) phosphorylated at specific sites recruits to RIPK1-FADD-caspase-8 complexes, driving gasdermin E (GSDME)-mediated cell lysis during mitotic arrest in ovarian cancer cells.^[88] These interactions have been identified primarily through yeast two-hybrid screening, which initially mapped FADD's DD-mediated bindings to TRADD and RIPK1, and affinity purification-mass spectrometry (AP-MS), revealing dynamic FADD complexes in untreated and stimulated cells.^[9]^[89] AP-MS data highlight FADD's role in broader networks, including energy metabolism and inflammation, beyond canonical death pathways.^[90]

References

[1]
Gene ResultFADD Fas associated via death domain [ (human)] - NCBI
Aug 19, 2025 · The adapter protein FADD provides an alternate pathway for entry into the cell cycle by regulating APC/C-Cdh1 E3 ubiquitin ligase activity.
[2]
Fas Associated Death Domain Protein - ScienceDirect.com
FADD, or Fas-associated death domain protein, is defined as a protein encoded by the FADD gene that plays a crucial role in apoptotic signaling by activating ...
[3]
FADD - FAS-associated death domain protein - UniProt
Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95 or TNFRSF1A, adapter protein FADD and the CASP8 protease; ...
[4]
FADD: a regulator of life and death - ScienceDirect.com
FADD is the key adaptor protein transmitting apoptotic signals mediated by the main death receptors (DRs).
[5]
Ubiquitination and degradation of the FADD adaptor protein ... - Nature
Jul 31, 2012 · Here we show that FADD is regulated by Makorin Ring Finger Protein 1 (MKRN1) E3 ligase-mediated ubiquitination and proteasomal degradation.Missing: review | Show results with:review
[6]
Cryo-EM structural analysis of FADD:Caspase-8 complexes defines ...
Feb 5, 2021 · Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions.
[7]
A novel protein that interacts with the death domain of Fas/APO1 ...
J Biol Chem. 1995 Apr 7;270(14):7795-8. doi: 10.1074/jbc.270.14.7795. Authors. M P Boldin ... Adaptor Proteins, Signal Transducing; Antigens, Surface; Carrier Proteins; DNA, Complementary; FADD protein, human; Fadd protein, mouse; Fas ...
[8]
FADD, a novel death domain-containing protein, interacts ... - PubMed
FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995 May 19;81(4):505-12. doi: 10.1016/ ...
[9]
and TNF receptor-induced cell death - PubMed
Jun 14, 1996 · Upon activation of these receptors, Fas/APO-1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can ...Missing: 1995 | Show results with:1995
[10]
TRADD-TRAF2 and TRADD-FADD interactions define two ... - PubMed
Here we show that TRADD directly interacts with TRAF2 and FADD, signal transducers that activate NF-kappa B and induce apoptosis, respectively.Missing: 1995 | Show results with:1995
[11]
Genomic Structure and Mapping of Human FADD, an Intracellular ...
Dec 15, 1996 · We report the characterization of the human FADD gene, which spans approximately 3.6 kb and contains two exons (286 and 341 bp) separated by a ...
[12]
602457 - FAS-ASSOCIATED VIA DEATH DOMAIN; FADD - OMIM
Gene Structure Kim et al. (1996) reported that the FADD gene contains 2 exons and spans approximately 3.6 kb.
[13]
FADD in Cancer: Mechanisms of Altered Expression and Function ...
According to The Human Protein Atlas, FADD protein levels are low in most normal tissues. In cancer, FADD is detected in all tumor types analyzed by RNA ...
[14]
FADD Gene - GeneCards | FADD Protein | FADD Antibody
The protein encoded by this gene is an adaptor molecule that interacts with various cell surface receptors and mediates cell apoptotic signals.
[15]
FADD as a key molecular player in cancer progression
Nov 8, 2022 · The FADD gene is mapped to the human chromosomal band 11q13 and encodes a functional FADD protein (about 23 kDa) composed of 208 amino acids.Missing: exons | Show results with:exons
[16]
Gene: FADD (ENSG00000168040) - Summary - Homo_sapiens
This gene has 2 transcripts (splice variants), 179 orthologues and is associated with 45 phenotypes. Transcripts. Show transcript table ...
[17]
Article Phosphorylation of FADD at Serine 194 by CKIα Regulates Its ...
The other three splice forms of CKIα (α, αL, and αS) were also tested and found to phosphorylate C-FADD at Ser194, suggesting that all CKIα isoforms are capable ...
[18]
dFADD, a novel death domain-containing adapter protein ... - PubMed
Oct 6, 2000 · dFADD contains a death domain that is highly homologous to the FADD death domain, and it also shares a novel domain with a Drosophila caspase ...Missing: TMF1 | Show results with:TMF1
[19]
Fadd | Drosophila melanogaster gene
Fas-associated death domain (Fadd) encodes an adaptor protein that functions downstream of the product of imd and upstream of the caspase encoded by Dredd in ...Missing: TMF1 | Show results with:TMF1
[20]
1E3Y: Death domain from human FADD/MORT1 - RCSB PDB
The structure comprises six alpha-helices joined by short loops and displays overall similarity to the death domain of the Fas receptor. The analysis of the ...Missing: crystal | Show results with:crystal
[21]
RCSB PDB - 1A1W: FADD DEATH EFFECTOR DOMAIN, F25Y MUTANT, NMR MINIMIZED AVERAGE STRUCTURE
### Summary of FADD Death Effector Domain from 1A1W
[22]
https://www.rcsb.org/structure/1FAD
[23]
https://www.nature.com/articles/nature07606
[24]
RCSB PDB - 1FAD: DEATH DOMAIN OF FAS-ASSOCIATED DEATH DOMAIN PROTEIN, RESIDUES 89-183
### Summary of FADD Death Domain from 1FAD
[25]
The Fas–FADD death domain complex structure unravels signalling ...
Dec 31, 2008 · The Fas–FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death.
[26]
CD95/Fas stoichiometry in future precision medicine - Nature
Apr 15, 2025 · We herein discuss the predicted conformation of CD95 at the plasma membrane and how these putative structures might account for the induction of the cell ...Cd95 Structure · How Does Cd95 Self-Associate... · Role Of Cd95 Signaling...<|control11|><|separator|>
[27]
Assembly and activation of the death-inducing signaling complex
Jun 4, 2025 · Using cryogenic electron microscopy (cryo-EM), we show that Fas and FADD death domains (DDs) form an asymmetric 7:5 oligomer, which promotes ...
[28]
FADDDED filaments coordinate complex IIa assembly during TNF ...
Aug 21, 2025 · Structurally, FADD consists of a C-terminal death domain (DD) ... The positions of amino acids comprising domains of FADD are indicated.Missing: boundaries | Show results with:boundaries
[29]
Signal transduction by DR3, a death domain-containing receptor ...
Nov 8, 1996 · Tumor necrosis factor receptor-1 (TNFR-1) and CD95 (also called Fas or APO-1) are cytokine receptors that engage the apoptosis pathway ...
[30]
TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD ... - PubMed
TRAIL induces apoptosis through two closely related receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Here we show that TRAIL-R1 can associate with TRAIL-R2, ...
[31]
Review RIPK-Dependent Necrosis and Its Regulation by Caspases
Oct 7, 2011 · The simultaneous deletion of caspase-8 and RIPK3 or FADD together with RIPK1 rescue embryonic development, suggesting that FADD and caspase ...
[32]
ubiquitin-mediated regulation of RIPK1/FADD/caspase-8 complexes
Jun 2, 2017 · In this review, we discuss the regulatory ubiquitin events that dictate the formation and activation of death-inducing complexes containing RIPK1/FADD/caspase- ...
[33]
Roles of RIPK3 in necroptosis, cell signaling, and disease - Nature
Oct 12, 2022 · RIPK1 not only positively regulates the activity of the necrosome complex after necrotic stimuli but also negatively regulates promiscuous basal ...
[34]
RIPK1 in necroptosis and recent progress in related pharmaceutics
Feb 10, 2025 · RIPK1 is a crucial protein kinase that regulates the necroptosis pathway. Increased expression of death receptor family ligands such as tumor necrosis factor ( ...
[35]
Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and ...
Phosphorylation of FADD on S191 (equivalent to S194 in humans) is the best-characterized covalent modification that regulates FADD function (17–19).
[36]
Bioluminescent RIPoptosome Assay for FADD/RIPK1 Interaction ...
Feb 20, 2023 · However, RIPoptosome formation can result in necroptosis including FADD-RIPK1-RIPK3-MLKL by caspase 8 inhibition or allergic inflammation ...
[37]
The adaptor protein FADD protects epidermal keratinocytes from ...
The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity. 2011 Oct 28;35(4):572-82. doi: ...
[38]
STING induces ZBP1-mediated necroptosis independently ... - Nature
Aug 20, 2025 · STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD. Nature (2025). https://doi.org/10.1038/s41586-025-09536-4. Download ...
[39]
Phosphorylated IRF3 promotes GSDME-mediated pyroptosis ...
Jul 1, 2025 · Phosphorylated IRF3 promotes GSDME-mediated pyroptosis through RIPK1/FADD/caspase-8 complex formation during mitotic arrest in ovarian cancer.
[40]
Essential roles of Atg5 and FADD in autophagic cell death - PubMed
We show that Atg5, which is known to function in autophagy, contributes to autophagic cell death by interacting with Fas-associated protein with death domain ( ...
[41]
Death sentence: The tale of a fallen endoplasmic reticulum
For instance, a death-inducing complex consisting of core autophagy protein ATG5, FADD, and caspase-8 is formed under ER stress in caspase-9-null cells, which ...
[42]
STING activates ZBP1-mediated PANoptosis to defend against HSV ...
Oct 27, 2025 · RNA-seq analysis revealed that STING depletion globally repressed pyroptosis, apoptosis, and necroptosis in mouse retinas (Figs. 3D and 4A).
[43]
Molecular characterization and immune association of Fas ...
Sep 24, 2024 · In this study, we characterized the FADD sequence of Tenebrio molitor (TmFADD) using molecular informatics to understand its role in immune surveillance of the ...
[44]
FADD: essential for embryo development and signaling from some ...
Mice with a deletion in the FADD gene did not survive beyond day 11.5 of embryogenesis; these mice showed signs of cardiac failure and abdominal hemorrhage.
[45]
Lack of FADD in Tie-2 expressing cells causes RIPK3-mediated ...
Sep 1, 2016 · Loss of FADD in Tie-2 expressing cells leads to embryonic lethality at E11.5 with heart defects, which can be rescued by RIPK3 knockout. (a) ...
[46]
A role for FADD in T cell activation and development - PubMed - NIH
FADD is a cytoplasmic adapter molecule that links the family of death receptors to the activation of caspases during apoptosis. We have produced transgenic ...Missing: Zhang 2000
[47]
The Fas-Associated Death Domain Protein (FADD) is Required in ...
Analysis of these mice revealed that FADD is required for Fas-induced apoptosis in B cells in order to maintain homeostasis in the spleen and lymph nodes.
[48]
Phosphorylation of FADD at serine 194 by CKIalpha regulates its ...
Aug 5, 2005 · Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities ... Authors. Elizabeth C Alappat , Christine Feig, ...Missing: CK1 | Show results with:CK1
[49]
FADD: a regulator of life and death - PubMed
Besides being an essential instrument in cell death, FADD is also implicated in proliferation, cell cycle progression, tumor development, inflammation, innate ...
[50]
Molecular evidence for the nuclear localization of FADD - PubMed
Since most studies have focused on the interaction of FADD with plasma membrane proteins, FADD's subcellular location is thought to be confined to the cytoplasm ...
[51]
Cellular Dynamics of Fas-Associated Death Domain in the ... - PubMed
Mar 12, 2024 · The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby ...
[52]
SPOTS: signaling protein oligomeric transduction structures ... - NIH
Analysis of DISC formation in patient-derived cell lines harboring the T225K mutant showed normal recruitment of FADD and procaspase-8 after anti-Fas ...
[53]
Phosphorylated FADD induces NF-κB, perturbs cell cycle ... - PNAS
Aug 30, 2005 · Using FADD knockout tissue culture cells, we demonstrate that expression of phosphorylated, but not nonphosphorylated, FADD results in NF-κB ...<|control11|><|separator|>
[54]
c-FLIP, A MASTER ANTI-APOPTOTIC REGULATOR - PMC - NIH
c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5) in a ligand-dependent and -independent fashion and forms an apoptosis inhibitory complex ...
[55]
Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy - PMC - NIH
c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5). This interaction in turn prevents Death-Inducing Signaling Complex (DISC) formation and ...
[56]
Controlling Cell Death through Post-translational Modifications of ...
The cryo-EM analysis revealed that procaspase-8 DEDs assemble into oligomeric structures that were named DED filaments [12]. The DED filaments provide a ...
[57]
FADD in Cancer: Mechanisms of Altered Expression and Function ...
Our data indicate that the phosphorylation status of FADD does not affect apoptosis [13], but FADD phosphorylation could affect apoptosis indirectly, as a ...
[58]
Ubiquitination and degradation of the FADD adaptor protein ...
Here we show that FADD is regulated by Makorin Ring Finger Protein 1 (MKRN1) E3 ligase-mediated ubiquitination and proteasomal degradation.Missing: inflammation | Show results with:inflammation
[59]
Protein phase change batteries drive innate immune signaling and ...
Sep 16, 2025 · These findings reveal DFD adaptors as biological phase-change materials that function like batteries, storing and privatizing energy for life-or ...
[60]
Fas-associated death domain protein and adenosine partnership
Jan 16, 2012 · This review discusses the possible link that could exist between the adenosine-dependent regulation of FADD in the inflammatory context of RA ...
[61]
FADD Negatively Regulates Lipopolysaccharide Signaling by ... - NIH
FADD negatively regulates lipopolysaccharide signaling by impairing interleukin-1 receptor-associated kinase 1-MyD88 interaction.
[62]
Signaling pathways and intervention therapies in sepsis - Nature
Nov 25, 2021 · This review focuses on the important signaling pathways, potential molecular mechanism, and pathway-associated therapy in sepsis.
[63]
Phosphorylated FADD induces NF-κB, perturbs cell cycle, and is ...
Aug 30, 2005 · To provide a link between p-FADD and NF-κB, cell culture studies demonstrated that overexpression of p-FADD leads to an increase in NF-κB ...
[64]
Mechanism of Fas-associated protein with death domain in ...
FADD plays a significant pro-carcinogenic role in HNSCC and is associated with poor prognosis. FADD can further regulate tumor cell proliferation by ...
[65]
induced Apoptosis in Burkitt's Lymphoma Cell Lines - PubMed
TRAIL is a potent inducer of apoptosis in sensitive cells and may be suitable for novel anti-cancer therapies aimed at inducing apoptosis via the activation of ...Missing: sensitization | Show results with:sensitization
[66]
Harnessing TRAIL-induced cell death for cancer therapy - Nature
Oct 4, 2022 · Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in a wide variety of cancer cells, both in vitro ...
[67]
FADD Functions as an Oncogene in Chr11q13.3-Amplified Head ...
May 15, 2025 · FADD expression was elevated in chr11q13. 3-amplified tumors and correlated with poor prognosis.
[68]
Prognostic and Clinicopathological Significance of FADD ... - MDPI
Phosphorylated FADD induces NF-kappaB, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas. Proc. Natl. Acad. Sci. USA 2005 ...2. Results · 2.4. Quantitative Evaluation... · 4. Materials And Methods
[69]
Absence or low expression of fas-associated protein with death ...
Absence or low expression of fas-associated protein with death domain in acute myeloid leukemia cells predicts resistance to chemotherapy and poor outcome.Missing: TRAIL | Show results with:TRAIL
[70]
Therapeutic targeting of TRAIL death receptors - Portland Press
Jan 11, 2023 · For instance, c-FLIP is known to inhibit DISC formation by competing with caspase-8/-10 for binding to FADD. FLIP is often overexpressed in ...
[71]
TRAIL pathway targeting therapeutics - PMC - NIH
Targeting the TRAIL pathway has been of interest in oncology, and although initial clinical trials of TRAIL receptor agonists (TRAs) showed limitations, novel ...
[72]
Necrostatin-1 and necroptosis inhibition - PubMed Central - NIH
Necrostatin-1 (Nec-1) is a RIP1-targeted inhibitor of necroptosis, a form of programmed cell death discovered and investigated in recent years.
[73]
An Inflammatory Perspective on Necroptosis - ScienceDirect.com
Mar 16, 2017 · Necroptosis is typically considered a highly pro-inflammatory mode of cell death, due to release of intracellular “danger signals” that promote ...Missing: hyperphosphorylation | Show results with:hyperphosphorylation
[74]
Identification of PANoptosis-related biomarkers and analysis of ...
Apr 29, 2024 · Furthermore, we showed that knockdown of FADD inhibited HNSCC cell proliferation, and inhibition of FADD might elevate the susceptibility of ...
[75]
Review FADD at the Crossroads between Cancer and Inflammation
This review focuses on recent knowledge of the biological roles of FADD, a pleiotropic molecule having multiple partners, and its impact in cancer, innate ...
[76]
SMAC Mimetic Birinapant plus Radiation Eradicates Human Head ...
Sep 15, 2016 · SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2.
[77]
Structural Study of the RIPoptosome Core Reveals a Helical ...
Aug 13, 2014 · In this study, we analyzed the overall structure of the RIP1 DD/FADD DD complex, the core of the RIPoptosome, by negative-stain electron microscopy and ...
[78]
RIP and FADD: two "death domain"-containing proteins can induce ...
The proteins RIP and FADD/MORT1 have been shown to interact with the "death domain" of the Fas receptor. Both of these proteins induce apoptosis in mammalian ...
[79]
The interaction between RIPK1 and FADD controls perinatal lethality ...
Jun 25, 2024 · Here, we describe Ripk1-mutant animals (Ripk1 R588E [RE]) in which the interaction between FADD and RIPK1 is disrupted, leading to embryonic lethality.
[80]
The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell ...
Jul 9, 2024 · ... RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a ...
[81]
Protein Kinase C Regulates FADD Recruitment and Death-inducing ...
Activation of protein kinase C (PKC) triggers cellular signals that inhibit Fas/CD95-induced cell death in Jur- kat T-cells by poorly defined mechanisms.
[82]
Protein kinase C modulates tumor necrosis factor-related apoptosis ...
In an in vitro binding assay, the intracellular domains of both TRAIL-R1 and TRAIL-R2 bound FADD: activation of PKC significantly inhibited this interaction ...
[83]
Phosphorylation of FADD by the kinase CK1α promotes ... - PMC - NIH
Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in ...Missing: S194 | Show results with:S194
[84]
Solution structure of N-TRADD and characterization of the ... - PubMed
The C-terminal of TRADD comprises the "death domain" that is responsible for association of TNFR1 and other death domain-containing proteins such as FADD and ...
[85]
STING induces ZBP1-mediated necroptosis independently of ...
These findings establish STING-driven ZBP1-mediated necroptosis as a central pathogenic mechanism in both caspase-8-deficient inflammation and ...
[86]
Beclin-1-mediated Autophagy Protects Against Cadmium-activated ...
Apr 20, 2017 · Beclin-1-mediated autophagy impairs the expression and function of cleaved caspase-8 to protect against Cd-induced activation of apopotosis through Fas/FasL ...
[87]
Evidence of complex formation between FADD and c-FLIP death ...
In this study, we provide evidence indicating that the death effector domain (DED) of FADD interacts directly with the death effector domain of human c-FLIP. In ...
[88]
FLIP and the death effector domain family - PubMed - NIH
Oct 20, 2008 · c-FLIP is a regulatory protein in the DED family that, along with FADD and caspases, can both regulate apoptosis and paradoxically promote ...
[89]
Phosphorylated IRF3 promotes GSDME-mediated pyroptosis ...
Phosphorylated IRF3 promotes GSDME-mediated pyroptosis through RIPK1/FADD/caspase-8 complex formation during mitotic arrest in ovarian cancer.
[90]
Characterisation of FADD interactome reveals novel insights into ...
Mar 25, 2021 · TfR1 is pre-associated with FADD and recruited into the DISC; moreover, our data reveal that TfR1 is also pre-associated with the death ...Missing: live | Show results with:live
[91]
A Dual Role for FADD in Human Precursor T-Cell Neoplasms - NIH
Dec 2, 2022 · Interactome Analysis Using DIA-MS Confirms FADD Participation in Energy Metabolism Processes. To confirm the participation of FADD in energy ...