Affinage

FASLG

Tumor necrosis factor ligand superfamily member 6 · UniProt P48023

Round 2 corrected
Length
281 aa
Mass
31.5 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FASLG encodes a type II transmembrane TNF superfamily ligand that triggers apoptosis by engaging preassembled trimeric Fas/CD95 receptors, with membrane-bound FasL being the principal cytotoxic form while metalloproteinase-cleaved soluble FasL is less potent and can antagonize membrane FasL activity (PMID:7505205, PMID:9427603). In cytotoxic T cells, NK cells, and iNKT cells, FasL mediates target cell killing and activation-induced cell death (AICD), with transcription controlled by NFAT/SP1 (IL-2 signaling), AP-1 (p38 MAPK), NFκB, and glucocorticoid receptor, and surface delivery regulated by SH3-domain interactions of its cytoplasmic polyproline region with Grb2, FBP17, PACSIN2, Tec kinases, and sorting nexins, as well as by palmitoylation-dependent lipid raft localization that governs ADAM10 processing (PMID:7530337, PMID:10556800, PMID:15928037, PMID:16770006, PMID:12023017, PMID:21368861). Beyond canonical immune cytotoxicity, FasL establishes immune privilege in tissues such as testis, mediates tumor endothelial immune barrier formation through VEGF-A/IL-10/PGE2-induced expression, drives platelet-RBC procoagulant signaling via Fas-dependent phosphatidylserine externalization on erythrocytes, participates in TGF-β3-dependent apoptosis during palatal fusion, and activates macrophages to a microbicidal state in synergy with IFN-γ (PMID:7566174, PMID:24793239, PMID:29952767, PMID:21593251, PMID:19380712). Hexagonal FasL arrangements at 10 nm spacing on DNA origami scaffolds produce optimal DISC activation, demonstrating that precise receptor clustering geometry is a critical determinant of signaling potency (PMID:34057291).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 High

    Identification of FasL as the TNF-family ligand for Fas/CD95 resolved the molecular identity of the death-inducing signal on cytotoxic T cells and established the Fas–FasL axis as a major apoptosis pathway.

    Evidence Expression cloning from cytotoxic T hybridoma; recombinant FasL in COS cells induces apoptosis in Fas+ targets

    PMID:7505205

    Open questions at the time
    • Downstream signaling intermediates (FADD, caspase-8 DISC assembly) not yet defined
    • Regulation of FasL expression unknown at this point
  2. 1995 High

    Demonstration that FasL mediates T-cell activation-induced cell death (AICD) and maintains immune privilege in testis established its dual role in immune homeostasis and tissue protection.

    Evidence Soluble Fas-Ig blockade prevents AICD in T hybridomas and human T clones; gld (FasL-deficient) testis grafts rejected whereas wild-type grafts survive indefinitely

    PMID:7528780 PMID:7530336 PMID:7530337 PMID:7566174

    Open questions at the time
    • Mechanism by which HIV exploits FasL for CD4 depletion only partially characterized
    • Relative contribution of FasL vs. perforin in different CTL contexts not resolved
  3. 1996 High

    Discovery that tumors express FasL to kill infiltrating Fas+ T cells ('Fas counterattack') revealed FasL as a mechanism of tumor immune evasion.

    Evidence FasL+ melanoma cells induce T-cell apoptosis in vitro; tumor growth is delayed in Fas-deficient lpr mice in vivo

    PMID:8910274

    Open questions at the time
    • Generalizability across tumor types debated
    • Whether tumor FasL expression is sufficient vs. necessary for immune escape not fully dissected
  4. 1998 High

    Identification of metalloproteinase-mediated FasL cleavage and the DcR3 decoy receptor established two independent mechanisms of FasL activity regulation: proteolytic shedding reduces killing potency, and soluble decoy receptor neutralizes ligand.

    Evidence FasL cleavage-site mutant retains full membrane-bound cytotoxicity; soluble FasL inhibits membrane FasL; DcR3 binds FasL and blocks apoptosis; DcR3 gene amplified in lung/colon tumors

    PMID:9427603 PMID:9872321

    Open questions at the time
    • Identity of the specific metalloproteinase(s) responsible in vivo not fully defined at this stage
    • Physiological contexts where DcR3 dominantly regulates FasL not established
  5. 1999 Medium

    Mapping of NFAT and SP1 binding to an overlapping FasL promoter element downstream of IL-2 signaling defined the transcriptional logic for activation-induced FasL expression in T cells.

    Evidence FasL promoter mutagenesis in IL-2-stimulated peripheral T cells; mutation of both SP1 and NFAT sites abolishes IL-2 response

    PMID:10556800

    Open questions at the time
    • Chromatin-level regulation and epigenetic control of the FasL locus not addressed
    • In vivo validation of SP1/NFAT requirement in T-cell AICD not performed
  6. 2000 Medium

    Evidence that Fas preassembles into trimers independently of FasL binding reframed the signaling model: FasL engages a pre-formed receptor complex rather than inducing receptor trimerization de novo.

    Evidence Biochemical and cellular Fas preassembly studies reviewed/synthesized

    PMID:10917832

    Open questions at the time
    • Stoichiometry of FasL trimer binding to preassembled Fas trimers not resolved
    • Higher-order clustering requirements for DISC assembly not defined
  7. 2002 High

    Discovery that FasL traffics through multivesicular bodies and is released on microvesicles, and that SH3-domain proteins FBP17 and PACSIN2 interact with its cytoplasmic polyproline region, established that FasL surface expression and secretion are actively regulated trafficking events.

    Evidence Subcellular fractionation showing FasL in melanosomes/MVBs with functional microvesicle release; pulldown/mass spectrometry identifying FBP17 and PACSIN2 as FasL cytoplasmic tail interactors

    PMID:12021310 PMID:12023017

    Open questions at the time
    • Functional consequence of each SH3 interaction on FasL surface delivery not individually dissected
    • Whether MVB-derived FasL microvesicles operate physiologically in immune killing unclear
  8. 2005 Medium

    Mapping of HIV-1 Nef-induced FasL transcription through p38 MAPK→AP-1 defined a viral hijacking mechanism for bystander T-cell killing via the FasL promoter.

    Evidence Dominant-negative p38, siRNA, chemical inhibitors, and FasL promoter AP-1 mutagenesis; HIV-1 bystander CD8 killing assay

    PMID:15928037

    Open questions at the time
    • In vivo relevance to HIV-associated CD4/CD8 depletion not directly tested
    • Relative contribution of Tat vs. Nef pathways to FasL induction in infected cells not resolved
  9. 2006 Medium

    Identification of glucocorticoid receptor competition with NFκB at a shared FasL promoter element, and ERK5-PKB-Foxo3a-mediated FasL repression, expanded the transcriptional regulatory network governing FasL expression to include stress and hormonal signaling.

    Evidence GR-NFκB steric occlusion at position -990 by ChIP and EMSA; ERK5/MEK5 KO fibroblasts show elevated Foxo3a-driven FasL

    PMID:16710360 PMID:16770006

    Open questions at the time
    • Integration of GR, NFκB, Foxo3a, NFAT, and AP-1 inputs at the endogenous locus not modeled
    • Tissue-specific dominance of individual transcription factors not established
  10. 2009 Medium

    Phage display identification of Tec kinases and sorting nexins as additional SH3-domain interactors of FasL's polyproline region broadened the set of candidate trafficking regulators, while demonstration that FasL synergizes with IFN-γ to activate macrophage microbicidal function established a non-apoptotic FasL signaling role.

    Evidence SH3 phage display library screen plus cellular pulldown; bone marrow-derived macrophage stimulation with FasL ± IFN-γ showing enhanced NO and parasite killing

    PMID:19380712 PMID:19807924

    Open questions at the time
    • Signaling pathway downstream of Fas in macrophage activation not defined
    • Functional requirement of individual SH3 interactors for FasL trafficking not validated by loss-of-function
  11. 2010 High

    Demonstration that FasL palmitoylation controls lipid raft localization and ADAM10-mediated processing, and that iNKT cell cytotoxicity depends almost exclusively on FasL, defined critical post-translational and cellular requirements for FasL function.

    Evidence Palmitoylation-site mutants reduce raft association, ADAM10 processing, and killing; FasL-deficient mice show near-complete loss of iNKT cytotoxicity in vivo

    PMID:20660713 PMID:21368861

    Open questions at the time
    • Whether palmitoylation is dynamically regulated during immune synapse formation unknown
    • Role of ADAM10 vs. other metalloproteinases in different cell types not systematically compared
  12. 2011 Medium

    Genetic epistasis showing TGF-β3 signaling is required for FasL-Fas-caspase pathway activation during palatal fusion extended FasL's developmental function beyond immune contexts.

    Evidence Tgf-β3 KO and conditional Tgfbr2 KO mice lack palatal FasL-Fas-caspase activity; ectopic FasL rescues apoptosis in Tgfbr2-deficient epithelium

    PMID:21593251

    Open questions at the time
    • How TGF-β3 transcriptionally or post-transcriptionally upregulates FasL in palate not defined
    • Contribution of FasL vs. other apoptotic pathways to normal palatogenesis not quantified
  13. 2013 Medium

    Discovery that ERα-induced MMP3 cleaves FasL to generate osteoclast-killing soluble FasL in bone, and that FasL participates in ischemic neuronal apoptosis via GluR6-Trx2-dependent procaspase-3 denitrosylation, revealed tissue-specific non-immune FasL functions.

    Evidence ERα KO osteoblasts, MMP3 inhibitor/siRNA, osteoclast co-culture; FasL antisense, TrxR2 knockdown, S-nitrosylation assays in rat hippocampal ischemia model

    PMID:22927007 PMID:23949220

    Open questions at the time
    • In vivo skeletal phenotype of FasL-deficient mice with respect to osteoclast apoptosis not fully characterized
    • Generality of GluR6-FasL-Trx2 pathway beyond hippocampal ischemia unknown
  14. 2014 High

    Identification of tumor endothelial FasL as a VEGF-A/IL-10/PGE2-driven immune barrier that selectively kills CD8+ T cells while sparing Tregs revealed FasL as a key effector of the immunosuppressive tumor vasculature, and D-cyclin repression of FasL in HSCs linked cell-cycle regulators to Fas-dependent apoptotic control of hematopoietic stem cells.

    Evidence In vitro endothelial FasL induction; genetic/pharmacologic FasL suppression in tumor-bearing mice; conditional triple D-cyclin KO in bone marrow with Fas/FasL/caspase-8 pathway analysis

    PMID:24793239 PMID:25087893

    Open questions at the time
    • Whether endothelial FasL barrier is reversible by anti-angiogenic therapy not demonstrated
    • Mechanism of D-cyclin-mediated FasL transcriptional repression not identified
  15. 2016 High

    Structural determination of the FasL–DcR3 complex revealed the molecular basis for decoy receptor recognition and enabled structure-guided FasL variants with enhanced apoptotic potency.

    Evidence X-ray crystallography of FasL:DcR3 complex; structure-based FasL mutations and glycosylation enhance Jurkat apoptosis

    PMID:27806260

    Open questions at the time
    • No crystal structure of FasL bound to its cognate receptor Fas/CD95 available
    • Structural basis for differential signaling between membrane-bound and soluble FasL not resolved
  16. 2018 High

    Platelet-expressed FasL was shown to drive both tissue apoptosis (neurons, retina) and procoagulant RBC phosphatidylserine exposure for thrombus formation, establishing FasL as a hemostatic and thrombotic effector beyond the immune system.

    Evidence Platelet-specific FasL conditional KO (PF4Cre+ FasLfl/fl); FasL−/− and FasR−/− mice in stroke, retinal injury, and arterial/venous thrombosis models

    PMID:26232171 PMID:29952767

    Open questions at the time
    • Whether platelet FasL contributes to pathological thrombosis in human disease not directly tested
    • Mechanism regulating FasL surface exposure on activated platelets not defined
  17. 2021 High

    Systematic testing of FasL spatial arrangements on DNA origami established that hexagonal geometry with 10 nm spacing maximizes DISC activation, providing the first nanometer-resolution map of optimal receptor clustering geometry for death signaling.

    Evidence DNA origami nanoagents with defined FasL geometries, spacings, and valencies; apoptosis kinetics in target cells

    PMID:34057291

    Open questions at the time
    • Whether these geometric requirements apply to physiological immune synapse FasL clustering unknown
    • Structural intermediates of DISC assembly at defined FasL geometries not visualized

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of FasL bound to its cognate Fas receptor, the full mechanism by which FasL cytoplasmic SH3 interactions coordinate trafficking to the immune synapse, and the signaling basis for non-apoptotic FasL functions in macrophages and other non-lymphoid cells remain unresolved.
  • No FasL–Fas co-crystal structure available
  • Individual contributions of SH3 interactors (Grb2, FBP17, PACSIN2, Tec kinases, sorting nexins) to FasL trafficking not resolved by loss-of-function
  • Signaling pathway downstream of Fas in non-apoptotic macrophage activation not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-5357801 Programmed Cell Death 6 R-HSA-162582 Signal Transduction 3 R-HSA-109582 Hemostasis 1 R-HSA-1266738 Developmental Biology 1
Partners
ADAM10DCR3FASFBP17GRB2MMP3PACSIN2

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 FasL (FASLG) was cloned as a type II transmembrane protein belonging to the TNF family, expressed on activated cytotoxic T cells; the recombinant protein induces apoptosis in Fas-expressing target cells, establishing FasL as the functional ligand for Fas-mediated apoptosis. Expression cloning using soluble Fas-Ig fusion protein to detect FasL on cytotoxic T hybridoma cells; recombinant FasL expressed in COS cells tested on Fas+ targets; Northern hybridization Cell High 7505205
1995 FasL-Fas interaction mediates activation-induced cell death (AICD) in T-cell hybridomas in a cell-autonomous manner: TCR crosslinking induces both FasL expression and Fas upregulation, and a soluble Fas-Ig fusion protein selectively blocks cell death without affecting activation. Soluble Fas-immunoglobulin fusion protein blockade; anti-FasL/Fas antibodies; T-cell hybridoma apoptosis assay with TCR crosslinking Nature High 7530336 7530337
1995 FasL mediates AICD in previously activated human T lymphocytes: TCR stimulation induces FasL mRNA/cytotoxic activity, and FasL antagonists inhibit AICD in T-cell clones and antigen-specific T-cell lines. Recombinant human FasL cytolysis assay; FasL antagonist blocking experiments; Fas+ target cell killing assays; RT-PCR for FasL mRNA The Journal of experimental medicine High 7528780
1995 FasL expressed by testicular Sertoli cells establishes immune privilege: normal testis grafts survived allogeneic transplantation indefinitely, whereas testis from gld mice (non-functional FasL) were rejected, demonstrating that FasL induces apoptotic death of activated Fas+ graft-rejecting T cells. Allogeneic transplantation of testis grafts from wild-type vs. gld mice under kidney capsule; Sertoli cell transplantation experiments Nature High 7566174
1995 FasL upregulation by HIV-1 Tat sensitizes T cells to CD95-mediated apoptosis: Tat strongly upregulates CD95L expression, and this mechanism is proposed to contribute to CD4+ T-cell depletion in AIDS. HIV-1 Tat treatment of T cells; CD95 ligand expression assay; TCR/CD4(gp120)-induced apoptosis with Tat pre-treatment Nature Medium 7539892
1996 Melanoma cells express FasL, which can induce apoptosis in Fas-expressing T cell infiltrates; FasL+ melanoma tumor growth is delayed in Fas-deficient lpr mice, establishing FasL as a mechanism of tumor immune escape ('Fas counterattack'). Immunostaining of metastatic lesions; in vitro apoptosis assay with FasL+ melanoma cells on Fas-sensitive targets; in vivo tumor formation in lpr (Fas-deficient) vs. wild-type mice Science High 8910274
1998 FasL is cleaved by a metalloproteinase to produce soluble FasL; membrane-bound FasL is the functional apoptosis-inducing form, while soluble FasL inhibits cytotoxicity of membrane-bound FasL, indicating that metalloproteinase-mediated shedding downregulates FasL killing activity. Deletion of cleavage site in human FasL; cytotoxicity assays comparing membrane-bound vs. soluble FasL on Jurkat cells and primary hepatocytes; metalloproteinase inhibitor experiments Nature medicine High 9427603
1998 DcR3 (decoy receptor 3) is a soluble TNF receptor family member that binds FasL and inhibits FasL-induced apoptosis; the DcR3 gene is amplified in ~50% of lung and colon tumors, suggesting tumors use DcR3 to escape FasL-dependent immune cytotoxic killing. Biochemical binding assay of DcR3 with FasL; FasL-induced apoptosis inhibition assay; genomic amplification analysis in primary tumors Nature High 9872321
2000 FasL binds preassembled trimeric Fas receptor: Fas preassembles into trimers independently of FasL, and this preassembly conditions subsequent FasL binding and death signal transduction. Biochemical and cellular studies of Fas preassembly (as reviewed/summarized in Perspective citing Chan et al. and Siegel et al.) Science Medium 10917832
2002 FasL is present in multivesicular bodies/melanosomes in melanoma cells and is released via FasL-bearing microvesicles that retain functional Fas-mediated apoptosis-inducing activity toward lymphoid cells. Subcellular fractionation; Western blot and flow cytometry of isolated melanosomes; co-localization of FasL with gp100/CD63; functional apoptosis assay of microvesicles on Jurkat cells The Journal of experimental medicine High 12021310
2002 The cytosolic polyproline region of FasL (CD178) interacts with SH3 domain proteins Grb2, FBP17, and PACSIN2 via SH3 domain binding; FBP17 and PACSIN2 are implicated in FasL trafficking and surface expression, while Grb2 was previously linked to TCR-to-FasL signaling. Pulldown from T-cell lysates with FasL cytosolic tail constructs; peptide mass fingerprinting; co-precipitation of overexpressed FasL with FBP17 and PACSIN2; SH3 domain mutation to confirm interaction FEBS letters Medium 12023017
2006 ERK5 promotes cell survival under osmotic stress by downregulating FasL expression via a PKB/Akt-dependent inhibition of Foxo3a transcription factor; loss of ERK5 or MEK5 leads to increased Foxo3a activity and elevated FasL, which acts as a positive feedback loop enhancing apoptosis. ERK5/MEK5 knockout fibroblasts treated with sorbitol; PKB activity and Foxo3a activity measurement; FasL expression analysis; genetic epistasis with dominant-negative constructs Cell death and differentiation Medium 16710360
2006 The glucocorticoid receptor (GR) represses the human FasL promoter by competing with NFκB for binding to a shared response element at position -990; GR binds this element in vitro and in chromatin, and its occupancy sterically occludes NFκB binding, representing a DNA-binding-dependent mechanism of GR-mediated FasL repression. FasL promoter deletion and mutagenesis; transient transfection reporter assays; electrophoretic mobility shift assay (EMSA); chromatin immunoprecipitation (ChIP); dominant-negative GR constructs FASEB journal Medium 16770006
2009 The FasL intracellular polyproline domain interacts with SH3 domains of Tec kinases and sorting nexins, as identified by phage display screening and verified by cellular pulldown assays; these interactions may regulate FasL function, transport, or processing. Human SH3 domain phage display library screen; pulldown experiments in cellular systems for Tec kinases and sorting nexins BMC immunology Medium 19807924
2010 FasL palmitoylation within its transmembrane domain is critical for efficient FasL-mediated killing and for FasL processing by ADAM10; FasL processing by ADAM10 occurs preferentially within cholesterol/sphingolipid-rich nanodomains (rafts) where Fas-FasL contact is efficient, and Fas-FasL interaction is required for efficient FasL processing. Palmitoylation mutants of FasL; ADAM10 processing assay; raft fractionation; FasL-EGFP cleavage reporter; cytotoxicity assays; siRNA knockdown Cell death & disease High 21368861
2010 Antigen-specific cytotoxicity of iNKT cells in vivo depends almost exclusively on the CD95/CD178 (Fas/FasL) pathway, correlates with CD1d expression levels and TCR affinity for glycolipid antigen, and can be used for tumor protection. In vivo cytotoxicity assay with iNKT cells from spleen, liver, thymus; genetic deficiency experiments (FasL-deficient vs. perforin-deficient mice); flow cytometry; tumor protection assay Journal of immunology High 20660713
2013 ERα signaling in osteoblasts regulates FasL cleavage and solubilization via upregulation of MMP3: 17β-estradiol (E2) activates ERα to increase MMP3 expression, MMP3 then cleaves membrane-bound FasL to release soluble FasL, which induces osteoclast apoptosis. EGFP-FasL cleavage reporter assay; specific MMP3 inhibitor; MMP3 siRNA knockdown; primary osteoblast cultures from ERαKO mice; conditioned media FasL quantification; osteoclast/osteoblast co-culture apoptosis assay Journal of bone and mineral research High 22927007
2014 Tumor endothelial FasL expression is cooperatively induced by tumor-derived VEGF-A, IL-10, and PGE2, enabling tumor vasculature to kill effector CD8+ T cells while sparing FoxP3+ Treg cells (which are protected by higher c-FLIP expression), establishing a tumor endothelial immune barrier. Immunostaining of human and mouse tumors; in vitro induction of FasL in endothelial cells by recombinant VEGF-A/IL-10/PGE2; cytotoxicity assays; genetic/pharmacologic FasL suppression in mice with CD8/Foxp3 T cell quantification; c-FLIP expression analysis in Tregs Nature medicine High 24793239
2015 Activated platelets express membrane-bound FasL on their surface; platelet-derived membrane-bound FasL induces Fas-dependent apoptosis in neurons, fibroblasts, and neuroblastoma cells; in vivo platelet depletion or platelet-specific FasL deletion (PF4Cre+ FasLfl/fl) reduces tissue apoptosis in stroke and retinal injury models. Flow cytometry of activated platelets; apoptosis assays with platelet membrane fractions on target cells; FasLΔm/Δm platelet knockout; PF4Cre+ FasLfl/fl conditional knockout mice; stroke model and NMDA retinal injury model Blood High 26232171
2016 Crystal structure of FasL in complex with its decoy receptor DcR3 was solved; structural comparison reveals that DcR3 recognizes invariant main-chain and conserved side-chain functionalities to bind multiple TNF ligands; structure-inspired FasL mutations and native glycosylation enhance FasL's ability to induce Jurkat cell apoptosis by reducing aggregation. X-ray crystallography of FasL:DcR3 complex; mutagenesis of FasL based on structure; Jurkat cell apoptosis assay with glycosylated vs. non-glycosylated FasL variants Structure High 27806260
2018 Platelet FasL and RBC FasR (CD95) mediate a direct cell-contact pathway in thrombus formation: platelet activation exposes FasL which activates Fas on RBCs, causing phosphatidylserine externalization on RBCs; genetic deletion of FasL or FasR reduces thrombin generation and thrombus formation in vitro and in vivo. FasL-/- and FasR-/- mice; in vitro thrombus formation assay; flow cytometry for PS exposure; thrombin generation assay; carotid artery injury and IVC ligation models; surgical specimens from thrombectomy patients The Journal of clinical investigation High 29952767
2018 High-dose osteocalcin (GluOC) triggers FasL upregulation on adipocyte plasma membranes via GPRC6A→cAMP→PKA→CREB-p300→FoxO1 signaling cascade; surface FasL then activates Fas on neighboring adipocytes, triggering MLKL phosphorylation/homotrimerization and Ca2+ influx (via TRPM7), generating ROS and inducing necroptosis. GPRC6A signaling pathway dissection; pharmacological inhibitors of PKA, ERK, SIK2; p300 activation assay; FoxO1/FasL Western blot; MLKL phosphorylation and homotrimerization assay; Ca2+ imaging; mitochondrial fragmentation analysis Cell death & disease Medium 30546087
2018 TNFα sensitizes hepatocytes to FasL-induced apoptosis through NFκB-mediated transcriptional upregulation and increased surface expression of Fas; genetic deletion, knockdown, or dominant-negative inhibition of NFκB p65 reduces Fas expression and blocks TNFα-induced sensitization, confirmed in vivo by hydrodynamic injection of p65 shRNA. Primary hepatocytes and cell lines; p65 knockout/siRNA/dominant-negative; Western blot for Fas; hydrodynamic tail-vein injection of p65 shRNA in mice; FasL-induced apoptosis assay Cell death & disease Medium 30185788
2021 DNA origami nanoagents with nanometer-precise hexagonal FasL arrangements with 10 nm inter-molecular spacing produce the fastest apoptosis kinetics and are 100× more efficient than soluble FasL, demonstrating that hexagonal receptor geometry and specific spacing are critical determinants of FasL-mediated death-inducing signaling complex (DISC) activation. DNA origami scaffolds with defined FasL arrangements; cell viability and time-to-death kinetics assays; comparison of different geometries (hexagonal, linear, random), spacings, and FasL valencies Small High 34057291
1999 FasL promoter activation by IL-2 is mediated through SP1 and NFAT binding to a GGGCGGAAA overlapping response element; mutation of the SP1 site (GGGCGG) or NFAT site (GGAAA) each partially reduced IL-2-induced FasL promoter activity, while mutation of both abolished it; the Egr site is not required for IL-2-induced activation. Transient transfection with FasL promoter deletion/mutation constructs; IL-2-treated peripheral T cells; nuclear expression analysis of SP1, NFAT, Egr-2, Egr-3 European journal of immunology Medium 10556800
2005 HIV-1 Nef induces FasL expression and T-cell bystander killing through a p38 MAPK→AP-1 pathway: p38 is required for Nef-induced AP-1 activation; the FasL promoter AP-1 enhancer element is required for Nef-mediated transcriptional activation, and p38 inhibition attenuates HIV-1-mediated bystander CD8 T-cell killing. Dominant-negative p38 isoforms; p38 siRNA; chemical inhibitors of p38; FasL promoter AP-1 element mutagenesis; reporter assays; HIV-1 bystander CD8 killing assay in vitro Blood Medium 15928037
2011 TGF-β3 signaling is required for FasL-Fas-caspase extrinsic apoptosis pathway activation during palatogenesis: FasL-Fas-caspase activity is detectable in wild-type palate fusion but absent in Tgf-β3-/- and K14-Cre;Tgfbr2fl/fl mice; FasL-Fas system inhibition causes persistence of the midline epithelial seam, and ectopic FasL rescues apoptosis in Tgfbr2-deficient epithelium. Tgf-β3 knockout and conditional Tgfbr2 knockout mice; FasL-Fas inhibition in palatal organ culture; ectopic FasL protein application; caspase activity measurement Journal of dental research Medium 21593251
2009 FasL synergizes with IFN-γ to activate macrophages to a microbicidal state (enhanced TNF, IL-6, NO secretion and killing of intracellular Leishmania major), while IL-4 suppresses this FasL/IFN-γ synergy, establishing a non-apoptotic signaling function for FasL in macrophage activation. Bone marrow-derived macrophage stimulation with FasL ± IFN-γ or IL-4; cytokine/NO measurement; intracellular parasite killing assay Journal of leukocyte biology Medium 19380712
2013 In cerebral ischemia/reperfusion, FasL mediates procaspase-3 denitrosylation and activation via the GluR6-FasL-Trx2 pathway: GluR6 antagonism inhibits I/R-induced FasL and Trx2 upregulation; FasL antisense oligodeoxynucleotides and TrxR2 knockdown inhibit procaspase-3 denitrosylation and reduce neuronal apoptosis. GluR6 antagonist (NS102); FasL antisense oligodeoxynucleotides; TrxR inhibitor (auranofin); TrxR2 antisense; lentiviral FasL/TrxR2 knockdown; S-nitrosylation assay; TUNEL staining; cresyl violet staining in rat hippocampus Cell death & disease Medium 23949220
2014 D-type cyclins repress FasL and Fas expression in hematopoietic cells; acute shutdown of all three D-cyclins in adult mouse bone marrow upregulates Fas and FasL expression, leading to Fas- and caspase-8-dependent apoptosis of hematopoietic stem and progenitor cells including quiescent HSCs. Conditional triple D-cyclin knockout in adult bone marrow; Fas/FasL mRNA and protein measurement; caspase-8 activation assay; flow cytometry of HSC populations Developmental cell Medium 25087893

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The biochemistry of apoptosis. Nature 5601 11048727
1998 Death receptors: signaling and modulation. Science (New York, N.Y.) 4733 9721089
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
1993 Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 2371 7505205
2003 Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2132 12887920
1996 Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 2048 8681376
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
1995 Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. The EMBO journal 1729 8521815
2000 Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature immunology 1532 11101870
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1995 Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 1390 7530337
1995 Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 1219 7530336
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1996 Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science (New York, N.Y.) 1074 8910274
2003 Mechanisms of caspase activation. Current opinion in cell biology 1028 14644197
1995 A role for CD95 ligand in preventing graft rejection. Nature 1022 7566174
1997 FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). The EMBO journal 1021 9184224
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
1995 A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. The Journal of biological chemistry 906 7536190
1995 Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 892 7539892
1995 Fas ligand mediates activation-induced cell death in human T lymphocytes. The Journal of experimental medicine 854 7528780
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2014 Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nature medicine 821 24793239
1997 Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 813 9215629
2010 Multiple common variants for celiac disease influencing immune gene expression. Nature genetics 801 20190752
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1998 Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 629 9872321
2002 Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. The Journal of experimental medicine 581 12021310
1998 Downregulation of Fas ligand by shedding. Nature medicine 578 9427603
1995 Fas and FasL in the homeostatic regulation of immune responses. Immunology today 505 8579749
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1997 Fas- and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950) 167 9317104
2017 Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance. Frontiers in immunology 162 28424702
2005 Impact of FASL-induced apoptosis in the elimination of tumor cells by NK cells. Molecular immunology 123 15607805
2012 Targeting the Fas/FasL signaling pathway in cancer therapy. Expert opinion on therapeutic targets 121 22239437
2010 Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency. Journal of immunology (Baltimore, Md. : 1950) 114 20660713
2002 The biological role of the Fas/FasL system during tumor formation and progression. Seminars in cancer biology 99 12147205
2001 Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells. Oncogene 91 11593384
2000 Neuronal FasL induces cell death of encephalitogenic T lymphocytes. Brain pathology (Zurich, Switzerland) 86 10885654
2019 TRAIL and FasL Functions in Cancer and Autoimmune Diseases: Towards an Increasing Complexity. Cancers 76 31072029
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