Affinage

FADD

FAS-associated death domain protein · UniProt Q13158

Length
208 aa
Mass
23.3 kDa
Annotated
2026-06-09
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FADD is the central bimodal adaptor that couples activated death receptors to apoptotic caspase activation while serving as a master switch governing alternative cell-death and inflammatory outcomes (PMID:8681376, PMID:9506948). Through its C-terminal death domain it binds Fas/APO-1, TNFR1, DR3, and the TRAIL receptors DR4/DR5, and through its N-terminal death-effector domain (DED) it recruits caspase-8 to nucleate the death-inducing signaling complex (DISC); FADD-deficient cells are completely resistant to apoptosis induced by these receptors, establishing FADD as their essential, non-redundant mediator (PMID:8681376, PMID:9506948, PMID:10894161, PMID:10894160). The DED is a six-helix amphipathic fold whose hydrophobic surface is required for caspase-8 binding, and it presents two distinct binding surfaces — the α1/α4 face preferred by cFLIP and the α2/α5 face preferred by procaspase-8 — that order a helical FADD–procaspase-8–cFLIP hetero-assembly tuning the extent of caspase-8 activation toward death versus survival (PMID:9582077, PMID:24577104, PMID:38710704). Structurally, FADD death domains and Fas death domains form a tetrameric bridge that acts as a stimulus-gated switch preventing accidental DISC assembly (PMID:19118384). Beyond apoptosis, FADD restrains RIPK1/RIPK3-MLKL necroptosis: loss of FADD or its inactivation unleashes RIP3-dependent programmed necrosis in T cells, intestinal epithelium, and skin, and FADD-null embryonic lethality is rescued by ablating RIPK1 or RIPK3 kinase activity, defining a FADD-caspase-8-cFLIPₘ complex that suppresses necroptosis and ZBP1-driven death during development and tissue homeostasis (PMID:18946037, PMID:20615958, PMID:21804564, PMID:22000287, PMID:21368761, PMID:22675671, PMID:36191211). FADD also has cell-cycle and non-apoptotic functions controlled by phosphorylation at Ser194(human)/Ser191(mouse) by CKIα downstream of KRAS, which promotes G2/M progression and proliferation and is reversed by an AK2/DUSP26 phosphatase complex (PMID:16061179, PMID:17553783, PMID:24548998, PMID:25628462). In innate immunity FADD is required for intracellular dsRNA-activated type I interferon production via RIP1/TBK1/IRF3, yet it also negatively regulates TLR4/IRAK1/MyD88 signaling and represses IFN responses through TRIM21 (PMID:15549108, PMID:17785432, PMID:21183682). Distinct post-translational marks redirect FADD function: SUMOylation at K120/125/149 routes it to mitochondrial Drp1-dependent necrosis, while ubiquitination by MKRN1 controls its abundance and DISC formation (PMID:22864571, PMID:27799292).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Established FADD as the physical link between death receptors and the apoptotic protease machinery, defining the adaptor concept for death-receptor signaling.

    Evidence Yeast two-hybrid and co-IP identifying FADD binding to Fas and TRADD and recruiting caspase-8; dominant-negative FADD blocking CD95 and TNF apoptosis

    PMID:8617770 PMID:8649383 PMID:8681376

    Open questions at the time
    • Did not resolve DISC stoichiometry or atomic interaction surfaces
    • Phosphorylation forms observed but functional role and kinase unknown
  2. 1998 High

    Genetic loss-of-function established FADD as an essential, non-redundant mediator specifically downstream of Fas, TNFR1, and DR3, and unexpectedly revealed a non-apoptotic role in T cell proliferation and development.

    Evidence FADD-knockout mice and FADD-deficient fibroblasts/T cells; FADD-DN transgenic and chimeric mouse readouts

    PMID:9450996 PMID:9506948 PMID:9521326

    Open questions at the time
    • Embryonic lethality obscured the mechanism of the proliferation defect
    • Receptor specificity for non-death-receptor stimuli unresolved
  3. 1998 High

    Defined the DED as a distinct six-helix fold whose unique hydrophobic surface mediates caspase-8 recruitment, giving the structural basis for DISC nucleation.

    Evidence NMR structure of the FADD DED with site-directed mutagenesis and apoptosis assays

    PMID:9582077

    Open questions at the time
    • Did not show the assembled receptor-FADD complex
    • Stoichiometry and higher-order oligomerization unresolved
  4. 1998 High

    Extended FADD beyond receptor-ligand apoptosis to innate antiviral death and ligand-independent death, broadening its functional scope.

    Evidence PKR-induced apoptosis blocked in FADD-null fibroblasts; anoikis blocked by dominant-negative FADD with caspase-8 readouts

    PMID:10508619 PMID:9843495

    Open questions at the time
    • Mechanism of ligand-independent caspase-8 activation not defined
    • Direct molecular link between PKR and FADD not established
  5. 2000 High

    Demonstrated FADD is a universal death-receptor adaptor recruited to endogenous TRAIL receptor DISCs, generalizing its role beyond Fas/TNFR1.

    Evidence Endogenous DISC immunoprecipitation for DR4/DR5 and FADD/caspase-8-deficient Jurkat cells

    PMID:10894160 PMID:10894161

    Open questions at the time
    • Did not address receptor-specific differences in DISC kinetics
    • Regulation by cFLIP not quantified
  6. 2005 High

    Identified CKIα as the kinase phosphorylating FADD at Ser194 in a cell-cycle-dependent manner, linking FADD to mitosis and proliferation rather than death.

    Evidence In vitro and in vivo kinase assays, CKI inhibitors, spindle-pole localization, and phospho-site mutant mice

    PMID:10640736 PMID:16061179 PMID:9590235

    Open questions at the time
    • Downstream effectors of phospho-FADD in mitosis not fully defined
    • How phosphorylation toggles death versus proliferation functions unclear
  7. 2007 High

    Connected FADD to intrinsic apoptosis and cell-cycle control via novel partner complexes, showing FADD acts in caspase-10 activation and is targeted by a phosphatase complex.

    Evidence Cell-free reconstitution of the AK2-FADD-caspase-10 complex; AK2/DUSP26 phosphatase dephosphorylating FADD with knock-in cell-cycle phenotypes

    PMID:17553783 PMID:17952061 PMID:24548998

    Open questions at the time
    • Physiological context of mitochondrial FADD-caspase-10 signaling not fully mapped
    • Cross-talk between phosphorylation cycle and DISC function incompletely resolved
  8. 2008 High

    Provided the atomic structure of the Fas-FADD death-domain complex, revealing a tetrameric bridge that acts as a stimulus-gated switch against accidental DISC assembly.

    Evidence 2.7 Å X-ray crystal structure of the human Fas-FADD death-domain complex

    PMID:19118384

    Open questions at the time
    • Did not capture the DED layer or caspase-8 recruitment geometry
    • In-cell relevance of the proposed switch not directly tested
  9. 2011 High

    Defined FADD's homeostatic role as a brake on RIPK1/RIPK3-dependent necroptosis, with loss causing necrosis-driven embryonic lethality and tissue inflammation.

    Evidence Tissue-specific FADD knockouts (IEC, keratinocyte) and Fadd/Rip1 and Fadd/Ripk3 double-knockout epistasis with developmental phenotyping

    PMID:20615958 PMID:21368761 PMID:21804564 PMID:22000287

    Open questions at the time
    • Tissue-specific differences in necroptosis drivers not fully explained
    • Molecular trigger that engages RIPK1 upon FADD loss not defined here
  10. 2012 High

    Established the FADD-caspase-8-cFLIPₗ trimeric complex as an enzymatically active survival module that suppresses RIPK3 signaling, reconciling FADD's pro-death and pro-survival roles.

    Evidence Fadd/Ripk3 and Fadd/cFlip/Ripk3 mouse knockout combinations with developmental rescue; MKRN1-mediated FADD ubiquitination controlling abundance

    PMID:22675671 PMID:22864571

    Open questions at the time
    • Quantitative threshold of caspase-8 activity distinguishing survival from death not defined
    • How complex composition is selected in vivo unresolved
  11. 2013 High

    Showed that phosphorylation of FADD at Ser191, together with caspase inactivation, licenses IFN-induced PKR-RIP1 necrosome formation, integrating FADD modification with necroptotic regulation.

    Evidence Phospho-mutant and FADD-deficient cells with IFN treatment, PKR knockdown, and RIP1/RIP3 inhibitors

    PMID:23898178

    Open questions at the time
    • Kinase responsible in the IFN context not pinned down here
    • Direct biochemical disabling of FADD by phosphorylation not structurally defined
  12. 2016 High

    Expanded FADD's non-apoptotic roles into metabolism and innate-immune restraint, showing phospho-FADD regulates transcriptional corepression and FADD dampens inflammatory signaling.

    Evidence FADD-RIP140 Co-IP with phospho-mimic and adipose knockout mice; FADD-IRAK1/MyD88 and FADD-TRIM21 interactions with cytokine and IFN readouts

    PMID:18256 PMID:21183682 PMID:27357657

    Open questions at the time
    • Direct enzymatic versus scaffolding contribution of FADD in these pathways unclear
    • How phosphorylation state coordinates metabolic and immune outputs unresolved
  13. 2017 High

    Identified SUMOylation as a switch routing FADD to mitochondrial Drp1-dependent necrosis, defining a post-translational code that diversifies FADD output.

    Evidence In vitro SUMOylation, SUMO-defective mutants, mitochondrial fractionation, and ischemic tissue analysis showing SUMO-FADD/Drp1/caspase-10 complex

    PMID:27799292

    Open questions at the time
    • SUMO ligase and dynamics in vivo not fully defined
    • Relationship between SUMO and phospho regulation not integrated
  14. 2020 High

    Resolved FADD's role within the RIPK1-caspase-8-FADD (FADDosome) as the regulator distinguishing apoptosis, necroptosis, ZBP1-driven death, and inflammatory caspase-8 output in vivo.

    Evidence Extensive mouse genetic epistasis across ZBP1, RIPK1, RIPK3, MLKL, GSDMD, caspase-8, OTULIN, and cGAS-STING backgrounds

    PMID:30741924 PMID:32075762 PMID:32362323 PMID:32428502 PMID:36191211

    Open questions at the time
    • Molecular determinants selecting among death modalities within the FADDosome not fully defined
    • Caspase-8-independent inhibition of necroptosis by FADD mechanistically unresolved
  15. 2024 High

    Provided atomic-resolution structures of the FADD-procaspase-8-cFLIP ternary DED assembly, explaining how the helical hetero-layer tunes limited caspase-8 activation for survival versus death.

    Evidence Cryo-EM and X-ray crystallography with structure-guided mutagenesis and functional apoptosis/necroptosis assays

    PMID:24577104 PMID:38710704

    Open questions at the time
    • In-cell dynamics of the assembled filament under physiological stimulation not captured
    • How upstream receptor geometry templates DED filament length unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the combination of FADD post-translational modifications (Ser194/191 phosphorylation, SUMOylation, ubiquitination) and partner availability is integrated in real time to select among apoptosis, necroptosis, proliferation, metabolism, and inflammation remains unresolved.
  • No unified model linking modification state to output decision
  • Quantitative thresholds and kinetics of DISC/FADDosome/SUMO-FADD complex partitioning unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 3 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3
Partners
AK2CASP8CFLARDR5/TNFRSF10BDRP1/DNM1LFASRIPK1TRADD
Complex memberships
AK2-FADD-caspase-10 (AFAC10) complexDISC (death-inducing signaling complex)FADD-caspase-8-cFLIP ternary complexFADDosome (RIPK1-caspase-8-FADD)

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 FADD (MORT1) was identified as a binding partner of the Fas/APO-1 death receptor and TRADD (the p55 TNF receptor-associated protein), and it recruits MACH (caspase-8), the most upstream enzymatic component in Fas/APO-1- and p55-R-induced cell death signaling cascades. Yeast two-hybrid, co-immunoprecipitation, cellular overexpression assays Cell High 8681376
1996 An N-terminal truncation of FADD (dominant-negative FADD) abrogates CD95-induced apoptosis, ceramide generation, and activation of caspase Yama/CPP32, and also blocks TNF-induced apoptosis without affecting NF-κB activation; dominant-negative FADD bound both CD95 and TNFR-1 and disrupted signaling complex assembly. Dominant-negative overexpression, caspase activity assays, NF-κB reporter assays, co-immunoprecipitation The Journal of biological chemistry High 8617770
1996 Mouse FADD/MORT1 associates with Fas in vivo only upon induction of cell death; a fraction of FADD is phosphorylated at serine/threonine residues, with both phosphorylated and unphosphorylated forms capable of binding Fas; a truncated dominant-negative form protects cells from Fas-mediated apoptosis by interfering with wild-type FADD–Fas interaction. Yeast two-hybrid, co-immunoprecipitation, dominant-negative stable expression, phosphorylation analysis Molecular and cellular biology High 8649383
1998 FADD-deficient embryonic fibroblasts are resistant to apoptosis induced by CD95, TNFR-1, and DR3, but not DR4, E1A, c-myc, or adriamycin, establishing FADD as an essential, non-redundant mediator specifically downstream of these death receptors. FADD-null mice die by embryonic day 11.5 with cardiac failure. FADD gene knockout mouse model, apoptosis assays in FADD-deficient fibroblasts, chimeric embryo analysis Science High 9506948
1998 Fas-induced apoptosis was completely blocked in FADD-deficient T cells (no redundant Fas apoptotic pathways), and activation-induced T cell proliferation was unexpectedly impaired despite IL-2 production, revealing a non-apoptotic role for FADD in T cell proliferation. FADD-knockout RAG-1-deficient chimeric mice, apoptosis assays, T cell proliferation assays Nature High 9521326
1998 NMR solution structure of the FADD death-effector domain (DED) reveals six antiparallel amphipathic alpha-helices resembling death domain fold; mutagenesis identified a hydrophobic region unique to the DED (absent in death domains) as vital for binding to caspase-8/FLICE and for apoptotic activity. NMR structure determination, site-directed mutagenesis, functional apoptosis assays Nature High 9582077
1998 Activation of dsRNA-dependent protein kinase PKR induces apoptosis through a FADD-dependent pathway; murine fibroblasts lacking FADD are almost completely resistant to dsRNA-mediated cell death, placing FADD downstream of PKR in innate antiviral apoptosis. Tetracycline-inducible PKR expression, FADD-deficient cell lines, apoptosis assays The EMBO journal High 9843495
1998 FADD is phosphorylated at serine 194 (human) in a cell-cycle-dependent manner — quantitatively phosphorylated at G2/M and unphosphorylated at G1/S; a 70-kDa cell-cycle-regulated kinase was identified that specifically binds the C-terminal half of FADD. Cell cycle synchronization (nocodazole, hydroxyurea), phosphorylation site mapping, co-immunoprecipitation with kinase Journal of immunology Medium 10640736
1998 FADD and the membrane-proximal cytoplasmic domain of Fas associate with kinases that phosphorylate FADD/MORT1, suggesting kinase signaling through the membrane-proximal region of Fas. GST-Fas fusion pulldown, in vitro kinase assay, phosphorylation analysis Journal of immunology Medium 9590235
1998 FADD dominant-negative transgenic mice show enhanced negative selection of autoreactive thymocytes and inhibited T cell activation by increasing apoptosis, demonstrating that FADD signaling can promote cell survival and proliferation under certain circumstances, not solely cell death. Transgenic mouse model expressing FADD-DN, thymocyte selection assays, T cell activation assays The EMBO journal High 9450996
1999 FADD is essential for multiple Fas-induced signaling events including activation of caspase-2, -3, -7, and -8, cleavage of BID, PKCδ, and PARP, and activation of p38 and JNK stress kinases and ceramide generation; FADD-deficient Jurkat cells are completely resistant to Fas-induced death. Chemical mutagenesis screen to isolate FADD-null Jurkat cells, complementation, caspase activity assays, ceramide measurement, kinase assays Cell growth & differentiation High 10616904
1999 Detachment-induced apoptosis (anoikis) is blocked by dominant-negative FADD in untransformed epithelial cells; caspase-8 activation is the initiating event in anoikis and is blocked by Bcl-2/Bcl-XL but not by soluble death receptor decoys, indicating FADD-dependent but ligand-independent activation of caspase-8. Dominant-negative FADD expression, caspase activity assays, soluble death receptor domain blocking, Bcl-2 overexpression Current biology Medium 10508619
2000 Apo2L/TRAIL induces homomeric and heteromeric complexes of DR4 and DR5 and stimulates endogenous FADD and caspase-8 recruitment and activation in non-transfected cells; TRADD and RIP do not bind DR4/DR5, indicating FADD is a universal adaptor for death receptors. Immunoprecipitation of endogenous DISC components, co-immunoprecipitation, caspase-8 activation assays Immunity High 10894160 10894161
2000 FADD/MORT1 and caspase-8 are recruited to both TRAIL-R1 and TRAIL-R2 independently of each other; FADD/MORT1- and caspase-8-deficient Jurkat cells expressing only TRAIL-R2 are resistant to TRAIL-induced apoptosis, establishing FADD as essential for TRAIL-R2-mediated apoptosis. Differential receptor precipitation, FADD/caspase-8-deficient Jurkat cells, DISC analysis Immunity High 10894160
2000 FIST/HIPK3 is a Fas-interacting serine/threonine kinase that binds Fas and causes FADD phosphorylation; overexpressed active FIST/HIPK3 impairs Fas ligand-induced JNK activation without affecting cell death. Yeast two-hybrid, co-immunoprecipitation, kinase activity assays, JNK activation assays The Journal of experimental medicine Medium 11034606
2001 T cell-specific FADD deficiency inhibits T cell development at the CD4−CD8− stage and reduces mature T cell numbers; the defect is not explained by impaired apoptosis or pre-TCR signaling, suggesting FADD is required for the proliferative phase of early T cell development through a receptor-independent mechanism. Conditional T cell-specific FADD knockout (genomic rescue approach), developmental stage analysis, TCR transgene rescue experiments Proceedings of the National Academy of Sciences High 11353862
2004 FADD-deficient mammalian cells are defective in intracellular dsRNA-activated gene expression including type I interferon production, and are highly susceptible to viral infection; this innate immune signaling pathway requires RIP1 and TBK1-mediated IRF-3 activation and is largely independent of TLR3 and PKR. FADD-deficient cell lines, viral infection assays, interferon production measurement, genetic epistasis with RIP1 and TBK1 Nature High 15549108
2005 Casein kinase Iα (CKIα) phosphorylates FADD at Ser194 both in vitro and in vivo; FADD-CKIα association regulates subcellular localization of FADD, with phospho-FADD colocalizing with CKIα on spindle poles in metaphase; CKIα inhibition diminishes FADD phosphorylation and blocks Taxol-induced mitotic arrest and mitogen-induced proliferation. In vitro kinase assay, in vivo phosphorylation with CKI inhibitors, subcellular localization (immunofluorescence), splenocyte proliferation assays, phosphorylation-site mutant mice Molecular cell High 16061179
2005 FADD negatively regulates TLR4/LPS signaling in endothelial cells by interacting with IRAK1 and MyD88 in a death-domain-dependent manner; LPS stimulation increases IRAK1-FADD interaction and recruits the IRAK1-FADD complex to MyD88, impairing JNK and PI3K activation; FADD deficiency leads to enhanced proinflammatory cytokine production. Co-immunoprecipitation of endogenous proteins, FADD-null cells, overexpression/reconstitution, cytokine production assays Molecular and cellular biology High 17785432
2007 Mitochondrial adenylate kinase 2 (AK2) mediates intrinsic apoptosis by translocating to the cytoplasm and forming an AK2-FADD-caspase-10 (AFAC10) complex; addition of purified AK2 to cell extracts induces caspase-10 activation via FADD and subsequently caspase-3 activation without affecting caspase-8. Co-immunoprecipitation, cell-free caspase activation assay with purified AK2, AK2 knockdown, subcellular fractionation Nature cell biology High 17952061
2007 Constitutive phosphorylation of FADD (FADD-D, serine 191 mimetic mutant) causes defective G0 and G1-to-S transition, with abnormalities in p130, p27 degradation, Rb phosphorylation, CDK2 kinase activity, and failure to upregulate FoxM1; phospho-FADD is mislocalized during cell cycle progression. FADD phosphorylation-mimic knock-in mice, cell cycle analysis, CDK2 kinase assay, subcellular localization The Journal of biological chemistry High 17553783
2008 The crystal structure of the human Fas-FADD death domain complex at 2.7 Å reveals a tetrameric arrangement of four FADD death domains bound to four Fas death domains; an opening of the Fas death domain exposes the FADD binding site and generates a Fas-Fas bridge, revealing a mechanistic switch that prevents accidental DISC assembly while allowing processive DISC clustering upon sufficient stimulus. X-ray crystallography at 2.7 Å, complex formation and isolation Nature High 19118384
2008 In T cells lacking FADD or caspase-8 activity, hyperactive autophagic signaling converts autophagy into a death process; caspase-8 is recruited to autophagic complexes through interaction with FADD:Atg5-Atg12 complexes; inhibition of autophagy or RIP kinase 1 (necroptosis inhibitor Nec-1) rescues FADD-deficient T cells from death. FADD-deficient and dominant-negative FADD T cells, autophagy inhibitors, dominant-negative Vps34, Atg7 shRNA, Nec-1 treatment, co-immunoprecipitation of FADD:Atg5-Atg12 Proceedings of the National Academy of Sciences High 18946037
2010 FADD interacts with TRIM21 E3 ubiquitin ligase; this interaction enhances TRIM21 ubiquitin ligase activity, and together they ubiquitinate IRF7, affect its phosphorylation, and repress IFN-α production during RNA virus infection; reduction of FADD or TRIM21 leads to higher IFN-α induction and lower virus titers. Co-immunoprecipitation, ubiquitination assay, IRF7 phosphorylation analysis, siRNA knockdown, viral infection assay The Journal of biological chemistry Medium 21183682
2010 FADD-deficient T cells undergo programmed necrosis (necroptosis) during late-stage normal T cell proliferation that is amplified in FADD-deficient T cells; this TCR-induced necroptosis requires RIP1 kinase activity (rescued by Nec-1) but does not require RIP3 or autophagy. Conditional T cell-specific FADD knockout, RIP1 kinase inhibitor Nec-1, T cell proliferation and death assays Proceedings of the National Academy of Sciences High 20615958
2011 IEC-specific FADD knockout causes RIP3-dependent programmed necrosis of intestinal epithelial cells; genetic deficiency of RIP3 prevents this pathology; CYLD deubiquitinase and TNF/MYD88 signaling drive the colitis but not the small intestinal disease, revealing different mechanisms of RIP3-dependent necrosis in colon versus small intestine. IEC-specific conditional FADD knockout mice, RIP3 genetic knockout epistasis, CYLD/TNF/MYD88 knockout crosses, microbiota elimination Nature High 21804564
2011 Epidermal keratinocyte-specific FADD deficiency triggers RIP3-mediated necroptosis causing inflammatory skin lesions; this necroptosis is partly dependent on CYLD deubiquitinase and TNF-TNFR1 signaling. Keratinocyte-specific conditional FADD knockout, RIP3 genetic epistasis, CYLD and TNF pathway analysis Immunity High 22000287
2011 FADD-deficient embryos contain elevated RIP1 levels and exhibit massive necrosis; RIP1 deficiency allows normal embryogenesis of FADD-deficient mice; conversely, the developmental defect of RIP1-deficient lymphocytes is partially corrected by FADD deletion; RIP1 deficiency fully restores T cell proliferation in FADD-deficient mice. Fadd/Rip1 double-knockout mouse generation and analysis, proliferation and death assays Nature High 21368761
2012 FADD, caspase-8, and cFLIPL form a trimeric survival complex; FADD-RIPK3 double-knockout mice develop normally; deletion of all three (FADD, cFLIP, RIPK3) rescues embryonic development; the FADD-caspase-8-cFLIPL complex enzymatic activity blocks RIPK3-dependent signaling, while cFLIPL blocks RIPK3-independent apoptosis by the FADD-caspase-8 complex. Fadd/Ripk3 and Fadd/cFlip/Ripk3 triple-knockout mouse models, embryonic development analysis Cell reports High 22675671
2012 FADD protein is ubiquitinated by MKRN1 E3 ligase leading to proteasomal degradation; MKRN1 knockdown stabilizes FADD protein, facilitates rapid DISC formation, and hypersensitizes cells to extrinsic apoptosis; MKRN1 and FADD also regulate necrosome formation and necroptosis. Co-immunoprecipitation, ubiquitination assay, MKRN1 knockdown, DISC precipitation, caspase cleavage assays, xenograft model Nature communications High 22864571
2013 IFN-induced RIP1/RIP3-mediated necrosis requires loss of FADD or caspase-8 inactivation; phosphorylation of FADD at serine 191 disables it and collaborates with caspase inactivation to allow IFN-activated necrosis; IFNs transcriptionally activate PKR, which then interacts with RIP1 to initiate necrosome formation. FADD-deficient and phospho-mutant cells, IFN treatment, PKR knockdown, RIP1/RIP3 inhibitors, necrosome complex analysis Proceedings of the National Academy of Sciences High 23898178
2014 FADD DED uses two binding surfaces (α1/α4 and α2/α5 helices): FLIP has preferential affinity for the α1/α4 surface of FADD DED, whereas procaspase-8 has preferential affinity for FADD's α2/α5 surface; tripartite FADD-FLIP-procaspase-8 intermediates assemble with FLIP DED1 α1/α4 surface interacting with procaspase-8 DED2 α2/α5 surface. Mutagenesis of DED binding surfaces, DISC stoichiometry analysis, functional apoptosis assays, binding affinity measurements Nature communications High 24577104
2014 AK2 forms a complex with DUSP26 phosphatase, stimulates DUSP26 activity, and this AK2/DUSP26 complex dephosphorylates FADD at Ser194/Ser191; AK2 deficiency enhances cell proliferation and tumor formation, and this anti-growth function is associated with its DUSP26-stimulating activity. Co-immunoprecipitation, in vitro phosphatase assay, AK2 knockdown/reconstitution, xenograft assay, AK2+/- MEF analysis Nature communications High 24548998
2015 CK1α phosphorylates FADD downstream of KRAS signaling to promote G2/M progression; phospho-FADD interacts with PLK1, AURKA, and BUB1 (G2/M kinases) as identified by mass spectrometry; deletion of CK1α in KRAS mutant mice abolishes FADD phosphorylation and suppresses lung cancer development. Conditional mouse models, immunohistochemistry, CK1α deletion in KRAS(G12D) mice, mass spectrometry of phospho-FADD interactome, CK1α inhibitor treatment Science signaling High 25628462
2016 FADD interacts with RIP140 (a corepressor for PPARα); FADD phosphorylation-mimic mutation (FADD-D) or FADD deficiency abolishes RIP140-mediated transcriptional repression, activating PPARα-driven fatty acid oxidation; FADD-D mice exhibit decreased adipose tissue mass and increased energy expenditure. Co-immunoprecipitation of FADD-RIP140, FADD phospho-mimic knock-in mice, adipose-specific FADD knockout, metabolic phenotyping EMBO molecular medicine High 27357657
2016 FADD overexpression promotes JNK1-mediated activation of E3 ubiquitin ligase ITCH to degrade cFLIPL; FADD interacts with procaspase-8, precludes cFLIPL from the DISC, negatively regulates cIAP2 and Bcl-2, and interacts with RIP1 and procaspase-8 to accomplish apoptotic cell death signaling. Co-immunoprecipitation, overexpression, ubiquitination assay, caspase activation assays Scientific reports Medium 26972597
2017 FADD is SUMOylated at multiple lysine residues (K120/125/149) by SUMO2 during calcium ionophore-induced necrosis and ischemic damage; SUMOylated FADD binds Drp1 and promotes its recruitment by mitochondrial fission factor (Mff) for mitochondrial fragmentation; caspase-10 (but not caspase-8) forms a ternary complex with SUMO-FADD/Drp1 on mitochondria and potentiates Drp1 oligomerization for necrosis. Co-immunoprecipitation, in vitro SUMOylation assay, SUMO-defective FADD mutants, mitochondrial fractionation, ischemic tissue analysis Molecular and cellular biology High 27799292
2017 RIPK3 kinase activity mediates embryonic lethality in FADD-deficient mice; Ripk3 kinase-inactive mutation rescues FADD-/- embryonic lethality, but Fadd-/-Ripk3Δ/Δ mice die after birth due to massive postnatal inflammation. Ripk3 kinase-dead knock-in crossed to FADD-knockout, embryonic and postnatal phenotyping Cell reports High 28445730
2019 In TNFR1 signaling, FADD is sufficient for TRAIL- but not TNF-induced apoptosis; FADD deficiency sensitizes more efficiently for TNFR1-mediated necroptosis than caspase-8 deficiency, indicating a caspase-8-independent inhibitory activity of FADD on TNF-induced necroptosis. CRISPR/Cas9 knockout of TRADD, RIPK1, and FADD individually and in combinations in RIPK3-expressing HeLa cells, apoptosis and necroptosis assays Cell death & disease Medium 30741924
2019 Classical NLRP3 inflammasome activation induces FADD secretion from human monocytes/macrophages through microvesicle shedding (not exosomes); FADD secretion requires K+ efflux, NLRP3, ASC, and caspase-1, but is distinct from pyroptosis-associated unspecific protein release and occurs independently of IL-1β release. NLRP3 inflammasome activation assays, microvesicle/exosome fractionation, FADD ELISA, K+ efflux measurement, caspase-1 inhibition Cell death & disease Medium 30804327
2019 IL-17A signals through IL-17R and Act1 to recruit FADD, which then mediates caspase-dependent apoptosis in retinal endothelial cells, causing retinal capillary degeneration in diabetes. IL-17A-/- mouse model, ex vivo retinal endothelial cell death assays, signaling pathway analysis with Act1/FADD Journal of diabetes and its complications Medium 31239234
2020 IEC-specific FADD or caspase-8 deficiency causes colitis dependent on MLKL-mediated epithelial necroptosis downstream of ZBP1 and TNFR1-RIPK1/RIPK3 signaling; in FADD-deficient IECs, both MLKL-independent ileitis requires caspase-8 and GSDMD (pyroptosis-like death), revealing dual regulation of intestinal inflammation by FADD. IEC-specific conditional knockout mice, multiple genetic epistasis crosses (ZBP1, RIPK1, RIPK3, MLKL, GSDMD, caspase-8), intestinal phenotyping Immunity High 32362323
2020 OTULIN-deficient hepatocyte apoptosis is completely prevented by FADD genetic ablation, and significantly protected by kinase-inactive RIPK1 knock-in, demonstrating that FADD-mediated apoptosis downstream of RIPK1 triggers liver disease pathogenesis in OTULIN-deficient mice. Liver-specific OTULIN knockout mice, FADD and RIPK1 kinase-dead genetic epistasis, liver histology and disease markers Cell reports High 32075762
2020 Caspase-8 and FADD prevent spontaneous ZBP1 upregulation; cells lacking FADD or caspase-8 show increased ZBP1 expression that is suppressed by reconstitution; ZBP1 ablation in caspase-8-deficient mice suppresses spontaneous MLKL phosphorylation; this mechanism involves a positive feedback loop requiring cGAS-STING-TBK1. Casp8 knock-in mouse model with FLAG-MLKL reporter, ZBP1/cGAS/STING genetic ablation, FADD/caspase-8 reconstitution in vitro Proceedings of the National Academy of Sciences High 36191211
2020 Caspase-8 inflammatory activity is regulated by its adapter FADD through the RIPK1-caspase-8-FADD (FADDosome) complex; ablation of one FADD allele prevents pathology in Casp8D387A/D387A Mlkl-/- mice; removing both FADD alleles results in early lethality prevented by co-ablation of RIPK1 or caspase-1, revealing a FADD-independent inflammatory role of caspase-8. Caspase-8 oligomerization-deficient and non-cleavable mutant mice, FADD/RIPK1/MLKL genetic epistasis crosses Immunity High 32428502
2023 cFLIPL suppresses Fas- or TRAIL-initiated NF-κB activation by inhibiting assembly of caspase-8/FADD/RIPK1 FADDosome complexes; cFLIPL's low affinity for FADD diminishes recruitment of FADD/RIPK1 to caspase-8 and thereby suppresses NF-κB activation and inflammatory cytokine production. cFLIP knockdown/deletion, FADDosome complex immunoprecipitation, NF-κB reporter assays, cytokine production measurement Cell reports Medium 37988267
2024 Cryo-EM and X-ray crystallography of human FADD-procaspase-8-cFLIP ternary DED complexes reveal atomic coordinates; a helical procaspase-8-cFLIP hetero-double layer promotes limited caspase-8 activation for cell survival; structure-guided mutagenesis confirms the role of the triple-FADD complex in caspase-8 activation and regulation of RIPK1. X-ray crystallography, cryo-EM, structure-guided mutagenesis, functional apoptosis and necroptosis assays Nature communications High 38710704

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 2050 8681376
2000 Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 818 10894161
1998 FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science (New York, N.Y.) 762 9506948
2000 FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 684 10894160
1996 FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. The Journal of biological chemistry 669 8617770
1998 Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 602 9521326
2011 FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 516 21804564
1998 A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. The EMBO journal 363 9450996
2011 Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 360 21368761
1997 Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 341 9208847
1998 Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. The EMBO journal 315 9843495
2013 Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proceedings of the National Academy of Sciences of the United States of America 305 23898178
2008 The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 302 19118384
2012 Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell reports 283 22675671
2008 FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells. Proceedings of the National Academy of Sciences of the United States of America 253 18946037
2011 The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 251 22000287
2020 FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells. Immunity 234 32362323
2015 MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD. Circulation research 234 26038570
2004 A FADD-dependent innate immune mechanism in mammalian cells. Nature 228 15549108
1998 NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature 208 9582077
1998 A role for FADD in T cell activation and development. Immunity 203 9586634
2017 Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nature medicine 191 28218919
1999 Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Current biology : CB 191 10508619
1992 Cloning, sequencing, and expression of the fadD gene of Escherichia coli encoding acyl coenzyme A synthetase. The Journal of biological chemistry 163 1460045
2010 FADD: a regulator of life and death. Trends in immunology 162 20576468
1999 FADD is required for multiple signaling events downstream of the receptor Fas. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 157 10616904
1998 TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. The Journal of biological chemistry 137 9488730
2000 Phosphorylation of FADD/ MORT1 at serine 194 and association with a 70-kDa cell cycle-regulated protein kinase. Journal of immunology (Baltimore, Md. : 1950) 133 10640736
2010 Fas-associated death domain (FADD) is a negative regulator of T-cell receptor-mediated necroptosis. Proceedings of the National Academy of Sciences of the United States of America 130 20615958
2020 AFP promotes HCC progression by suppressing the HuR-mediated Fas/FADD apoptotic pathway. Cell death & disease 129 33009373
2005 Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities. Molecular cell 129 16061179
2020 Caspase-8-Dependent Inflammatory Responses Are Controlled by Its Adaptor, FADD, and Necroptosis. Immunity 127 32428502
2000 Ionizing radiation and chemotherapeutic drugs induce apoptosis in lymphocytes in the absence of Fas or FADD/MORT1 signaling. Implications for cancer therapy. The Journal of experimental medicine 123 10620618
2000 FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor. The EMBO journal 120 10698935
2005 Phosphorylated FADD induces NF-kappaB, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas. Proceedings of the National Academy of Sciences of the United States of America 119 16109772
2002 PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway. Oncogene 116 11803475
2012 The roles of FADD in extrinsic apoptosis and necroptosis. BMB reports 111 23010170
2012 Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis. Nature communications 110 22864571
1996 A mouse Fas-associated protein with homology to the human Mort1/FADD protein is essential for Fas-induced apoptosis. Molecular and cellular biology 107 8649383
2017 Long Noncoding RNA H19/miR-675 Axis Promotes Gastric Cancer via FADD/Caspase 8/Caspase 3 Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 104 28848149
2005 Nonapoptotic functions of FADD-binding death receptors and their signaling molecules. Current opinion in cell biology 103 16226446
2000 FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits fas-mediated Jun NH(2)-terminal kinase activation. The Journal of experimental medicine 103 11034606
2020 ATRX/EZH2 complex epigenetically regulates FADD/PARP1 axis, contributing to TMZ resistance in glioma. Theranostics 94 32194873
2001 T cell-specific FADD-deficient mice: FADD is required for early T cell development. Proceedings of the National Academy of Sciences of the United States of America 92 11353862
2007 AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10. Nature cell biology 81 17952061
2006 Prolonged activation of ERK1,2 induces FADD-independent caspase 8 activation and cell death. Apoptosis : an international journal on programmed cell death 79 16538383
2006 Morphine promotes Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-kappaB pathways. Journal of neuroimmunology 76 16529824
2018 FADD at the Crossroads between Cancer and Inflammation. Trends in immunology 75 30401514
2001 Protein kinase C regulates FADD recruitment and death-inducing signaling complex formation in Fas/CD95-induced apoptosis. The Journal of biological chemistry 75 11581255
1999 FADD/MORT1, a signal transducer that can promote cell death or cell growth. The international journal of biochemistry & cell biology 73 10399313
2014 Differential affinity of FLIP and procaspase 8 for FADD's DED binding surfaces regulates DISC assembly. Nature communications 70 24577104
2014 The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth. Nature communications 65 24548998
2022 Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis. Proceedings of the National Academy of Sciences of the United States of America 63 36191211
2019 Redundant and receptor-specific activities of TRADD, RIPK1 and FADD in death receptor signaling. Cell death & disease 63 30741924
1997 Characterization of reaper- and FADD-induced apoptosis in a lepidopteran cell line. Molecular and cellular biology 63 9001220
2010 Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production. The Journal of biological chemistry 62 21183682
2010 Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination. Journal of immunology (Baltimore, Md. : 1950) 61 21068410
2005 FADD and caspase-8 are required for cytokine-induced proliferation of hemopoietic progenitor cells. Blood 54 15905188
2007 FADD negatively regulates lipopolysaccharide signaling by impairing interleukin-1 receptor-associated kinase 1-MyD88 interaction. Molecular and cellular biology 53 17785432
1998 FADD gene therapy for malignant gliomas in vitro and in vivo. Human gene therapy 52 9694158
2020 OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis. Cell reports 50 32075762
2012 The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-κB by TRAIL. Cell death & disease 47 23096115
2005 Nuclear localized phosphorylated FADD induces cell proliferation and is associated with aggressive lung cancer. Cell cycle (Georgetown, Tex.) 47 16258269
2021 The lncRNA H19-Derived MicroRNA-675 Promotes Liver Necroptosis by Targeting FADD. Cancers 45 33499244
2019 The classical NLRP3 inflammasome controls FADD unconventional secretion through microvesicle shedding. Cell death & disease 44 30804327
2004 FADD and its phosphorylation. IUBMB life 44 15545216
2016 FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis. Scientific reports 43 26972597
2015 Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer. Science signaling 43 25628462
2008 Japanese encephalitis virus infection activates caspase-8 and -9 in a FADD-independent and mitochondrion-dependent manner. The Journal of general virology 43 18632964
2004 Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes. Cell death and differentiation 43 15017386
2017 RIPK3 Mediates Necroptosis during Embryonic Development and Postnatal Inflammation in Fadd-Deficient Mice. Cell reports 42 28445730
2017 RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice. Cell death and differentiation 41 28574501
2019 FADD in Cancer: Mechanisms of Altered Expression and Function, and Clinical Implications. Cancers 40 31569512
2013 FADD expression is associated with regional and distant metastasis in squamous cell carcinoma of the head and neck. Histopathology 40 23763459
1998 Phosphorylation of FADD/MORT1 and Fas by kinases that associate with the membrane-proximal cytoplasmic domain of Fas. Journal of immunology (Baltimore, Md. : 1950) 40 9590235
2023 cFLIPL acts as a suppressor of TRAIL- and Fas-initiated inflammation by inhibiting assembly of caspase-8/FADD/RIPK1 NF-κB-activating complexes. Cell reports 36 37988267
2006 Molecular roles of MAP kinases and FADD phosphorylation in prostate cancer. Histology and histopathology 36 16437387
2000 FADD and TRADD expression and apoptosis in primary hepatocellular carcinoma. World journal of gastroenterology 36 11819561
2019 Diabetes induces IL-17A-Act1-FADD-dependent retinal endothelial cell death and capillary degeneration. Journal of diabetes and its complications 35 31239234
2022 FADD as a key molecular player in cancer progression. Molecular medicine (Cambridge, Mass.) 34 36348274
2017 SUMO-Modified FADD Recruits Cytosolic Drp1 and Caspase-10 to Mitochondria for Regulated Necrosis. Molecular and cellular biology 34 27799292
2009 DNA amplification and expression of FADD in oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 34 20040024
2007 Constitutive phosphorylation mutation in Fas-associated death domain (FADD) results in early cell cycle defects. The Journal of biological chemistry 34 17553783
2023 Ginsenoside Rb1 promotes the activation of PPARα pathway via inhibiting FADD to ameliorate heart failure. European journal of pharmacology 32 37001580
2017 Decreased linear ubiquitination of NEMO and FADD on apoptosis with caspase-mediated cleavage of HOIP. Biochemical and biophysical research communications 32 28189684
2006 Emerging roles for the death adaptor FADD in death receptor avidity and cell cycle regulation. Cell cycle (Georgetown, Tex.) 32 17102623
2000 Rapid B cell apoptosis induced by antigen receptor ligation does not require Fas (CD95/APO-1), the adaptor protein FADD/MORT1 or CrmA-sensitive caspases but is defective in both MRL-+/+ and MRL-lpr/lpr mice. International immunology 32 10744653
2018 FADD (Fas-Associated Protein With Death Domain), Caspase-3, and Caspase-8 and Incidence of Ischemic Stroke. Stroke 31 30354994
2014 Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout. Cell death and differentiation 30 24971483
2004 Fas-associated protein with death domain (FADD)-independent recruitment of c-FLIPL to death receptor 5. The Journal of biological chemistry 29 15485835
2012 Cyclin D1 and FADD as biomarkers in head and neck squamous cell carcinoma. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 28 22323434
2012 FADD protein release mirrors the development and aggressiveness of human non-small cell lung cancer. British journal of cancer 27 22669160
2016 Effects of anti-depressant treatments on FADD and p-FADD protein in rat brain cortex: enhanced anti-apoptotic p-FADD/FADD ratio after chronic desipramine and fluoxetine administration. Psychopharmacology 25 27259485
2016 FADD is a key regulator of lipid metabolism. EMBO molecular medicine 25 27357657
2016 Clinical Implications of FADD Gene Amplification and Protein Overexpression in Taiwanese Oral Cavity Squamous Cell Carcinomas. PloS one 25 27764170
2002 Hepatocyte Fas-associating death domain protein/mediator of receptor-induced toxicity (FADD/MORT1) levels increase in response to pro-apoptotic stimuli. The Journal of biological chemistry 25 12167637
2024 Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis. Nature communications 24 38710704
2005 Recruitment of TRADD, FADD, and caspase 8 to double-stranded RNA-triggered death inducing signaling complexes (dsRNA-DISCs). Apoptosis : an international journal on programmed cell death 24 15711932
2003 Dominant negative MORT1/FADD rescues mice from CD95 and TNF-induced liver failure. Hepatology (Baltimore, Md.) 24 12500197
2017 FADD, Caspase-3, and Caspase-8 and Incidence of Coronary Events. Arteriosclerosis, thrombosis, and vascular biology 23 28302628

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