Affinage

FGL2

Fibroleukin · UniProt Q14314

Length
439 aa
Mass
50.2 kDa
Annotated
2026-04-28
97 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGL2/fibroleukin is a dual-function protein operating at the intersection of coagulation and immune regulation. As a membrane-associated type II transmembrane protein, FGL2 acts as a serine prothrombinase that directly cleaves prothrombin to thrombin via a catalytic Ser89 residue in a phospholipid-, calcium-, and factor Va-dependent manner, driving fibrin deposition in viral hepatitis, xenograft rejection, and vascular thrombosis (PMID:11994472, PMID:12840059, PMID:15100314). As a secreted oligomeric effector produced by regulatory T cells and other immune cells, FGL2 binds FcγRIIB and FcγRIII on antigen-presenting cells and CD8+ T cells, inducing apoptosis via caspase 3/7, inhibiting dendritic cell maturation and T cell proliferation, and suppressing adaptive immunity in infection, transplantation, and tumor microenvironments (PMID:18991288, PMID:18097026, PMID:38902261, PMID:30683885). Transcription of FGL2 is induced by viral nucleocapsid protein through HNF4α, by IFN-γ through STAT1/Sp1/PU.1, and by TNF-α through NF-κB and p38 MAPK pathways in a cell-type-specific manner, while its immunosuppressive function requires the C-terminal fibrinogen-related globular domain and is modulated by disulfide-linked tetramerization (PMID:10187767, PMID:12594208, PMID:16709865, PMID:23127799, PMID:36243222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Identification of FGL2 as a novel cell-surface prothrombinase on reticuloendothelial cells resolved the long-standing question of how MHV-3 infection triggers fibrin deposition and hepatic necrosis independent of classical coagulation cascades.

    Evidence Northern blot, in situ hybridization, and immunohistochemistry in MHV-3-infected mouse livers

    PMID:9371581 PMID:9782336

    Open questions at the time
    • Catalytic mechanism and active-site residues not yet identified
    • No purified protein reconstitution to confirm direct prothrombinase activity
  2. 1999 High

    Demonstration that the MHV-3 nucleocapsid protein induces fgl2 transcription via a specific promoter element (-372 to -306) established the first transcriptional mechanism linking viral pathogenicity to FGL2-mediated coagulation, subsequently refined to show HNF4α binding at a -331/-325 cis-element.

    Evidence Promoter-reporter assays with deletion mapping in CHO cells (1999); EMSA and site-directed mutagenesis of N protein domains (2003)

    PMID:10187767 PMID:12594208

    Open questions at the time
    • How nucleocapsid protein activates HNF4α remains unclear
    • Relevance to human hepatitis viruses not established
  3. 2001 High

    Cloning of human FGL2 and identification of its domain architecture (type II transmembrane protein with C-terminal fibrinogen-related domain) provided the structural framework for understanding both prothrombinase and later-discovered immunoregulatory functions.

    Evidence Cloning, heterologous expression, functional prothrombinase assay, FISH mapping to 7q11.23

    PMID:11170750

    Open questions at the time
    • No crystal structure available
    • Function of the C-terminal fibrinogen-related domain beyond prothrombinase not yet explored
  4. 2002 High

    Biochemical reconstitution of purified FGL2 into phospholipid vesicles proved it is a bona fide serine protease that cleaves prothrombin directly, with Ser89 as the catalytic residue and requirements for phosphatidylserine, calcium, and factor Va — establishing FGL2 as a non-classical prothrombinase.

    Evidence In vitro reconstitution of baculovirus-expressed FGL2 with kinetic analysis and Ser89 mutagenesis

    PMID:11994472

    Open questions at the time
    • Structural basis for resistance to classical serine protease inhibitors unexplained
    • Whether FGL2 has substrates beyond prothrombin is unknown
  5. 2003 High

    The fgl2 knockout mouse demonstrated that FGL2 is essential for macrophage procoagulant activity and fibrin-mediated liver necrosis during MHV-3 infection, providing definitive genetic proof of its in vivo prothrombinase function and establishing its non-redundancy with classical coagulation factors.

    Evidence Gene-targeted fgl2−/− mouse with peritoneal macrophage procoagulant assay, histopathology, and survival analysis

    PMID:12840059

    Open questions at the time
    • Whether sFGL2 immunosuppressive function also contributes to the infection phenotype was not dissected
    • Compensatory mechanisms in fgl2−/− mice not characterized
  6. 2003 High

    Mapping of constitutive and cytokine-induced fgl2 transcription revealed cell-type-specific promoter architecture: Sp1/Sp3 and Oct-1/Ets-1 drive basal expression in endothelial cells, while IFN-γ signals through STAT1/Sp1/PU.1 in macrophages and p38 MAPK mediates virus-induced expression.

    Evidence EMSA, heterologous Drosophila Schneider cell expression, promoter deletion analysis (2003); p38 and ERK inhibitor studies in macrophages (1998); IFN-γ/STAT1/PU.1 pathway in knockout mice (2006)

    PMID:12752447 PMID:16709865 PMID:9822700

    Open questions at the time
    • Chromatin-level regulation of the FGL2 locus not characterized
    • Integration of multiple simultaneous cytokine signals not modeled
  7. 2004 High

    FGL2 was established as the endothelial prothrombinase mediating acute vascular rejection thrombosis in xenotransplantation — fgl2−/− donor hearts were devoid of intravascular thrombosis — and was also shown to be required for LPS-induced pregnancy loss and normal early embryonic vascular development.

    Evidence Porcine FGL2 prothrombinase assay and fgl2−/− heterotopic heart xenograft model (2004); fgl2−/− timed matings and LPS abortion model (2004)

    PMID:14742694 PMID:15100314

    Open questions at the time
    • Whether sFGL2 immunoregulatory function contributes to graft rejection alongside prothrombinase activity
    • Mechanism of selective embryonic hemorrhage in fgl2−/− mice unclear
  8. 2008 High

    Discovery that FGL2 binds FcγRIIB and FcγRIII on APCs and induces B cell apoptosis, and that Treg-derived FGL2 is a critical effector of Treg suppressive activity, revealed a second, immunoregulatory function entirely distinct from the prothrombinase activity — transforming FGL2 from a coagulation factor into a dual-function immune-coagulation mediator.

    Evidence SPR binding assays, FcγRIIB−/− cell lines and mice, skin allograft model (2008); fgl2−/− Treg suppression assays, anti-FGL2 antibody blockade, bone marrow reconstitution (2008)

    PMID:18097026 PMID:18991288

    Open questions at the time
    • Precise binding epitope on FcγRIIB not mapped
    • Whether FGL2 signals through FcγRIII with distinct downstream consequences unknown
  9. 2011 High

    Extension of FGL2–FcγRIIB signaling to hepatic ischemia-reperfusion injury and to experimental arthritis broadened the pathophysiological scope, showing FGL2 induces sinusoidal endothelial cell apoptosis via FcγRIIB and that membrane FGL2 prothrombinase is required for fibrin-driven joint inflammation.

    Evidence Dual fgl2−/− and FcγRIIB−/− mouse I/R models with caspase-3/TUNEL readouts (2011); fgl2−/− anti-CII arthritis model (2011)

    PMID:21469939 PMID:21756857

    Open questions at the time
    • Whether apoptotic and prothrombinase functions operate simultaneously in the same tissue
    • Role of sFGL2 vs mFGL2 in arthritis not dissected
  10. 2012 High

    Structural characterization revealed that secreted FGL2 is a disulfide-linked tetramer (Cys94/97/184/187), with the C-terminal globular domain containing the immunosuppressive motifs; unexpectedly, monomeric FGL2 showed greater immunosuppressive potency than the oligomer, indicating oligomerization modulates rather than enables function.

    Evidence Cysteine-to-alanine mutagenesis, non-reducing SDS-PAGE, peptide blockade, deglycosylation

    PMID:23127799

    Open questions at the time
    • High-resolution structure not available
    • Physiological regulation of oligomeric state unknown
  11. 2019 High

    FGL2 was identified as a tumor immune-evasion molecule: glioblastoma stem cell-derived FGL2 suppresses GM-CSF-induced CD103+ DC differentiation by inhibiting NF-κB, STAT1/5, and p38 signaling, and FGL2 prothrombinase in pulmonary endothelium drives in situ thrombosis in pulmonary hypertension.

    Evidence FGL2-KO glioma cells in immunocompetent vs immunodeficient mice (2019); fgl2−/− mice in hypoxia-induced PH models (2019)

    PMID:30683885 PMID:31580221

    Open questions at the time
    • Whether FGL2 suppresses DCs through FcγRIIB or an independent receptor in the brain microenvironment
    • Therapeutic window for anti-FGL2 in tumors not defined
  12. 2022 High

    A human homozygous truncating FGL2 mutation (p.V205fs) lacking the C-terminal domain failed to suppress T cell proliferation and was rescued by full-length recombinant FGL2, providing the first human genetic validation that the fibrinogen-related domain is essential for immunosuppressive function.

    Evidence Whole-exome sequencing, HEK293 expression of truncated vs full-length protein, Treg suppression assay with rescue

    PMID:36243222

    Open questions at the time
    • Clinical phenotype associated with this mutation not fully delineated in the timeline
    • Whether prothrombinase activity is also affected by this truncation not tested
  13. 2022 Medium

    FGL2 was shown to regulate IgE class-switching: TFH cell-derived FGL2 represses antigen-specific IgE responses, and FGL2 in neutrophils interacts with mucolipin 3 (MCOLN3) to regulate calcium-dependent autophagy and NET formation, revealing additional cell-type-specific functions.

    Evidence Conditional Fgl2 deletion in TFH/TFR cells with food-allergy model (2022); scRNA-seq and FGL2-MCOLN3 interaction studies in neutrophils (2022)

    PMID:35767958 PMID:35926777

    Open questions at the time
    • FGL2–MCOLN3 interaction not confirmed by reciprocal IP or structural studies
    • Whether FGL2 regulates IgE through FcγRIIB on B cells or another mechanism not resolved
  14. 2024 High

    Conditional deletion of Fgl2 in CD8+ T cells demonstrated cell-autonomous immunosuppression: CD8+ T cell-derived FGL2 binds FcγRIIB on the same cells to trigger caspase 3/7-mediated apoptosis and T cell exhaustion, and macrophage-secreted FGL2 acts on CD8+ T cells via the same receptor, establishing a paracrine and autocrine FGL2–FcγRIIB axis that limits antitumor and antiviral CD8+ T cell responses.

    Evidence Conditional Fgl2 KO in CD8+ T cells, FcγRIIB conditional KO, caspase assays, chronic LCMV and tumor models (2024); Fgl2−/− mice plus Fcgr2b conditional KO in CD8+ T cells across melanoma models (2025)

    PMID:38902261 PMID:40125553

    Open questions at the time
    • Signaling intermediates downstream of FcγRIIB in CD8+ T cells not fully mapped
    • Whether autocrine vs paracrine FGL2 has differential potency in vivo remains unclear
  15. 2025 Medium

    FGL2 was linked to regulation of immune checkpoint molecules: tumor cell FGL2 sustains PD-L1 expression via mTORC1-mediated TFEB phosphorylation that blocks lysosomal PD-L1 degradation, and FGL2 promotes CD47 expression through Src/PKCα, identifying FGL2 as an upstream regulator of multiple immune checkpoint pathways.

    Evidence FGL2-KO hepatoma cells with mTORC1/TFEB pathway analysis (2026 pub); CRISPR FGL2 KO with Src/PKCα proteomics and CD47 reconstitution in brain tumor models (2025)

    PMID:41380903 PMID:41629991

    Open questions at the time
    • Direct physical interaction between FGL2 and mTORC1 or Src not demonstrated
    • Whether these checkpoint regulatory mechanisms operate through the same FcγRIIB axis or independently is unknown
    • Single-laboratory findings await independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for FGL2's dual prothrombinase and immunosuppressive activities; how the switch between membrane-bound and secreted forms is regulated; the precise signaling cascade downstream of FcγRIIB engagement by FGL2; and whether anti-FGL2 therapeutic strategies can selectively target immunosuppressive versus coagulant functions.
  • No crystal or cryo-EM structure of FGL2
  • Mechanism of membrane-to-secreted form switching unknown
  • Full downstream signaling pathway from FcγRIIB upon FGL2 engagement not mapped
  • No clinical trials targeting FGL2 reported in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0048018 receptor ligand activity 5 GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 4
Pathway
R-HSA-109582 Hemostasis 6 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4
Partners
FCGR2BFCGR3HNF4AMCOLN3STAT1TYROBP

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 FGL2 is a novel prothrombinase expressed on the cell surface of endothelial cells and macrophages (Kupffer cells) in the liver following MHV-3 infection; it generates thrombin from prothrombin, leading to fibrin deposition and hepatic necrosis. Expression is tissue-specific and restricted to reticuloendothelial cells. Northern analysis, in situ hybridization, immunohistochemistry in MHV-3-infected mice Journal of virology High 9371581 9782336
2002 FGL2 is a serine protease that directly cleaves prothrombin to thrombin; activity requires phosphatidylserine-containing membranes, calcium, and is greatly enhanced by factor Va. Serine residue Ser89 is critical for catalytic activity. The enzyme is not inhibited by classical serine protease inhibitors (antithrombin III, aprotinin, PMSF) but is abolished by diisopropylfluorophosphate. In vitro reconstitution of purified baculovirus-expressed FGL2 into phospholipid vesicles, kinetic analysis, site-directed mutagenesis of Ser89, truncation constructs Journal of immunology (Baltimore, Md. : 1950) High 11994472
2001 Human FGL2 encodes a 439-amino-acid type II integral membrane protein with a C-terminal fibrinogen-related domain; it functions as a prothrombinase (serine protease) that directly cleaves prothrombin to thrombin. The gene is single-copy, located at 7q11.23, with two exons. Cloning, heterologous expression, functional prothrombinase assay, radiation hybrid mapping, FISH Genomics High 11170750
1999 The nucleocapsid (N) protein of virulent MHV-3 (but not non-pathogenic strains) induces transcription of the fgl2 prothrombinase gene. A region from -372 to -306 upstream of the ATG start site in the fgl2 promoter is responsive to nucleocapsid protein. Co-transfection of nucleocapsid expression constructs with fgl2 promoter-luciferase reporter in CHO cells, use of parental and recombinant MHV strains The Journal of biological chemistry High 10187767
2003 Induction of fgl2 by the MHV-3 nucleocapsid protein requires host hepatic nuclear factor-4 alpha (HNF4α) binding to a -331/-325 HNF4 cis-element in the fgl2 promoter. Specific residues (Gly-12, Pro-38, Asn-40, Gln-41, Asn-42) in domain 1 of the N protein are required for fgl2 transcription induction. HNF4α is unexpectedly present in peritoneal macrophages. Site-directed mutagenesis of N protein domains, EMSA, luciferase reporter assays, deletion mapping of fgl2 promoter The Journal of biological chemistry High 12594208
2003 Constitutive fgl2 transcription in vascular endothelial cells is controlled by a 119 bp minimal promoter region containing a complex positive regulatory domain (-87 to -49) bound by Sp1/Sp3, Oct-1, and Ets-1. Both Sp1 and Sp3 are required for constitutive expression, and viral-induced fgl2 expression also requires this PRD. 5'-RACE, primer extension, EMSA, heterologous expression in Drosophila Schneider cells, promoter deletion/mutation analysis European journal of biochemistry High 12752447
1998 MHV-3-induced fgl2 expression in macrophages is mediated via p38 MAPK signaling; selective p38 inhibition (SB203580) abolishes fgl2 mRNA, protein, and procoagulant activity. ERK activation also contributes to fgl2 functional activity but not mRNA/protein levels. p38 and ERK form interconnected cascades in macrophage activation. Western blot, immunoprecipitation, in vitro kinase assay, selective kinase inhibitors (SB203580, PD98059) in vitro and in vivo The Journal of biological chemistry High 9822700
2006 IFN-γ induces fgl2 expression in macrophages through a STAT1-dependent pathway involving composite cis-elements Sp1/Sp3 and GAS/PU.1; PU.1 interaction with the GAS/ETS site determines macrophage-specific fgl2 induction. TNF-α induces fgl2 in endothelial cells. Cytokine-induced hepatic apoptosis in vivo is dependent on fgl2 (absent in fgl2-/- mice). Promoter-reporter assays, EMSA, in vivo cytokine infusion in fgl2+/+ vs fgl2-/- mice, cell-type-specific induction experiments Journal of immunology (Baltimore, Md. : 1950) High 16709865
2003 Fgl2/fibroleukin deficiency in mice completely abolishes macrophage procoagulant response to MHV-3 infection, markedly reduces fibrin deposition and liver necrosis, and improves survival. This establishes fgl2 as essential for immune-coagulation in viral hepatitis. Gene-targeted fgl2-/- mouse, peritoneal macrophage procoagulant assay, histopathology, survival analysis The Journal of clinical investigation High 12840059
2008 FGL2 binds specifically to FcγRIIB and FcγRIII receptors on antigen-presenting cells (B cells, macrophages, dendritic cells), as shown by flow cytometry and surface plasmon resonance. FGL2 inhibits dendritic cell maturation and induces apoptosis in FcγRIIB+ B cells; these effects are abrogated in FcγRIIB-/- cells. In vivo, recombinant FGL2 prolongs allograft survival only in FcγRIIB+/+ mice. Flow cytometry, surface plasmon resonance (SPR), FcγRIIB-/- mice, A20 vs A20IIA1.6 cell lines, skin allograft model European journal of immunology High 18991288
2008 FGL2 is produced by CD4+CD25+ Foxp3+ regulatory T cells (Tregs) and mediates their suppressive activity. Deficiency of FGL2 in Treg cells results in impaired Treg suppression, increased T cell proliferation, Th1 polarization, increased B cell antibody production, and spontaneous autoimmune glomerulonephritis. Anti-FGL2 antibody completely inhibits Treg activity in vitro. FGL2 induces B cell apoptosis via FcγRIIB. fgl2-/- mice and bone marrow reconstitution, in vitro Treg suppression assays, anti-FGL2 antibody blockade, flow cytometry, immunization experiments Journal of immunology (Baltimore, Md. : 1950) High 18097026
2012 Native secreted FGL2 exists as a ~260 kDa oligomer composed of four ~65 kDa monomers linked by disulfide bonds. Cysteines at positions 94, 97, 184, and 187 in the coiled-coil domain are required for oligomerization. Monomeric FGL2 has lower APC-binding affinity but greater immunosuppressive activity than oligomeric FGL2. The functional immunosuppressive motifs map to the C-terminal globular domain. Site-directed mutagenesis of cysteine residues, SDS-PAGE under reducing/non-reducing conditions, deglycosylation, peptide blockade assay, SWISS-MODEL structural analysis The international journal of biochemistry & cell biology High 23127799
2004 FGL2 is expressed on vascular endothelial cells of xenografts undergoing acute vascular rejection (AVR); porcine fgl2 generates thrombin from human prothrombin in vitro. Hearts from fgl2-/- mice transplanted into rats are devoid of intravascular thrombosis associated with AVR, whereas fgl2+/+ and fgl2+/- grafts develop thrombosis, directly establishing fgl2 as the endothelial procoagulant mediating AVR-associated thrombosis. Cloning of porcine fgl2, recombinant protein prothrombinase assay, fgl2-/- heterotopic heart xenograft model, histopathology Journal of immunology (Baltimore, Md. : 1950) High 15100314
2011 FGL2 binding to FcγRIIB on sinusoidal endothelial cells (SECs) induces apoptosis of SECs and hepatocytes during hepatic ischemia-reperfusion injury. FGL2-/- or FcγRIIB-/- mice are markedly protected from liver injury, with dramatically reduced caspase-3 and TUNEL staining and improved survival. In vitro, FGL2 induces apoptosis of SECs from WT but not FcγRIIB-/- mice. fgl2-/- and FcγRIIB-/- mouse ischemia-reperfusion model, caspase-3 staining, TUNEL, AST/ALT measurement, in vitro SEC apoptosis assay Journal of hepatology High 21756857
2011 mFGL2 prothrombinase is upregulated in the joints of mice with collagen-induced arthritis, associated with fibrin deposition in synovium. fgl2-/- mice fail to develop clinical or histological manifestations of arthritis after anti-collagen II antibody injection, directly demonstrating the necessity of mFGL2 prothrombinase activity for experimental arthritis. fgl2-/- mice in anti-CII arthritis model, qRT-PCR, immunohistochemistry, clinical scoring Scandinavian journal of rheumatology Medium 21469939
2019 FGL2 expressed by glioblastoma stem cells suppresses NF-κB, STAT1/5, and p38 signaling in dendritic cells, thereby inhibiting GM-CSF-induced CD103+ DC differentiation in the brain and tumor-draining lymph nodes. This impairs antitumor immunity and promotes GBM progression in immune-competent but not immunodeficient mice. FGL2-knockout glioma cells in immune-competent vs immunodeficient mice, DC-deficient mice, signaling pathway analysis Nature communications High 30683885
2021 FGL2-producing glioma cells recruit macrophages into the tumor microenvironment and induce macrophages to secrete CXCL7 via CD16/SyK/PI3K/HIF1α pathway. CXCL7 in turn enhances the stem-like functionality of glioma cells, forming a FGL2-CXCL7 paracrine loop that promotes tumor progression. Mass cytometry, RNA sequencing, neutralizing antibody blockade, pathway inhibition in immunocompetent mice Cancer letters Medium 33676940
2004 fgl2 is required for physiological early embryonic development; fgl2-/- embryos show hemorrhage at the anti-mesometrial pole and selective occult loss before gestation day 11.5. LPS-induced abortion in mice requires fgl2 (abortions do not occur in fgl2-/- matings), placing fgl2 in the pathway linking inflammatory cytokines/LPS to pregnancy loss via coagulation. fgl2-/- knockout mouse, timed matings, PCR genotyping of embryos, LPS injection model, immunostaining Molecular human reproduction Medium 14742694
2001 Th1 cytokines (TNF-α, IFN-γ) upregulate fgl2 mRNA in fetal trophoblast and secondary decidua, leading to fibrin deposition and abortion. OX-2 glycoprotein is co-expressed at the same sites and is reduced by Th1 cytokines; anti-OX-2 raises the abortion rate while recombinant OX-2 reduces it, indicating OX-2 can counteract fgl2-mediated coagulation/abortion. In situ hybridization for fgl2 and OX-2, anti-OX-2 antibody treatment, recombinant OX-2 administration, fibrin staining in CBA/J mouse pregnancy models Molecular human reproduction Medium 11160845
2013 Soluble FGL2 (sFGL2) secretion by CD4+ T cells is induced by TNF-α and IFN-γ via MAPK signaling, specifically through c-Jun N-terminal kinase (JNK) phosphorylation; JNK inhibition significantly reduces sFGL2 secretion. Neither p38 MAPK nor ERK1/2 show significant changes. In vitro stimulation of human CD4+ T cells with TNF-α or IFN-γ, JNK inhibitor treatment, ELISA for sFGL2, Western blot for MAPK phosphorylation The Journal of surgical research Medium 23664593
2014 C5a/C5aR pathway promotes FGL2 expression in liver sinusoidal endothelial cells and macrophages through ERK1/2 and p38 MAPK signaling during viral fulminant hepatitis. C5aR-/- mice show reduced FGL2 expression and coagulation. In vitro C5a stimulates TNF-α production in CD11b+ cells, which then promotes FGL2 expression in endothelial cells. C5aR-/-, Fgl2-/-, Tnfα-/- mice, in vitro C5a stimulation, ERK1/2 and p38 inhibitors, sorted liver cell populations Journal of hepatology High 25200905
2022 FGL2 directly interacts with mucolipin 3 (MCOLN3) in neutrophils, which regulates calcium influx and initiates autophagy, leading to neutrophil extracellular trap (NET) formation. Neutrophil-specific FGL2 promotes NETs, which exacerbate liver injury in fulminant viral hepatitis via fibrin deposition and inflammation. Single-cell RNA sequencing, adoptive transfer of FGL2-expressing neutrophils, DNase 1 NET depletion, interaction studies between FGL2 and MCOLN3 Cellular and molecular gastroenterology and hepatology Medium 35926777
2024 CD8+ T cell-derived FGL2 mediates cell-autonomous immunosuppression by binding to FcγRIIB expressed on the same CD8+ T cells, triggering caspase 3/7-mediated apoptosis. Conditional deletion of Fgl2 specifically in CD8+ T cells prolongs their persistence, reduces T cell exhaustion phenotype, and improves antitumor control. FcγRIIB-deficient CD8+ T cells are insensitive to Fgl2 regulation. Conditional Fgl2 knockout in antigen-specific CD8+ T cells, transcriptomic analysis, caspase 3/7 apoptosis assay, tumor models, chronic LCMV infection Nature communications High 38902261
2025 Macrophage-secreted FGL2 dampens CD8+ T cell responses by binding FcγRIIB on CD8+ T cells and inducing their apoptosis in a cell-autonomous (non-APC-intermediary) manner. FcγRIIB-/- CD8+ T cells are insensitive to Fgl2 regulation. Macrophages are identified as the major tumor-microenvironment source of Fgl2 in melanoma and multiple cancer types. Fgl2-/- mice, Fcgr2b conditional knockout in CD8+ T cells, melanoma tumor models, scRNA-seq of human tumors JCI insight High 40125553
2019 FGL2 prothrombinase in pulmonary vascular endothelium contributes to in situ thrombosis and vascular remodeling in pulmonary hypertension (PH). FGL2 knockout attenuates PH development, reduces PAR1 (proteinase-activated receptor 1) expression, and decreases platelet overactivation in hypoxia-induced PH models. Fgl2-/- mice in monocrotaline-rat and hypoxia-mouse PH models, PAR1 expression analysis, platelet activation assays, immunohistochemistry Journal of applied physiology Medium 31580221
2019 FGL2 regulates IKK/NF-κB signaling in intestinal epithelial cells and lamina propria dendritic cells. FGL2-/- mice show stronger NF-κB activation and more severe DSS-induced colitis. Recombinant FGL2 inhibits proinflammatory cytokine production and NF-κB signaling in HT-29 cells and rescues the FGL2-/- colitis phenotype. FGL2-/- mice in DSS colitis model, recombinant FGL2 rescue, NF-κB signaling analysis in IECs and LPDCs, flow cytometry of DC maturation markers Molecular immunology Medium 31743856
2022 FGL2 expressed by T follicular helper (TFH) cells represses IgE responses. Conditional deletion of Fgl2 in TFH (and TFR) cells, but not TFR cells alone, increases antigen-specific IgE levels and IgE-mediated anaphylaxis in a food-allergy model. Fgl2 and CD39 are downregulated in TFH cells under optimal IgE sensitization conditions. Conditional Fgl2 deletion in TFH/TFR cells, food-allergy model with timed Ag sensitizations, flow cytometry of IgE+ GC B cells, anaphylaxis assay Cell reports Medium 35767958
2022 A human homozygous truncating mutation in FGL2 (c.614_617del:p.V205fs) retains the N-terminal domain but lacks the C-terminal immunoregulatory domain. The truncated protein fails to suppress T cell proliferation. Full-length recombinant FGL2 rescues the impaired Treg suppressive function, establishing the C-terminal domain as essential for FGL2's immunosuppressive activity. Whole-exome sequencing, HEK293 transfection/immunoblotting, flow cytometry of Treg function, in vitro Treg suppression assay with full-length vs truncated FGL2 The Journal of allergy and clinical immunology High 36243222
2004 In the hamster epididymis, FGL2 (HEP64) is secreted by principal cells of the proximal cauda epididymidis and specifically coats nonviable spermatozoa as part of a 'death cocoon' complex composed of FGL2 monomers (64 kDa) assembled into disulfide-linked oligomers of 260 and 280 kDa. FGL2 does not bind to viable spermatozoa. Expression screening of cDNA library, Northern blot, in situ hybridization, immunohistochemistry, immunoelectron microscopy, SDS-PAGE, microsequencing of isolated death cocoon fraction The Journal of biological chemistry Medium 15377663
2022 FGL2 interacts with Tyrobp (DAP12) in cutaneous squamous cell carcinoma cells, as shown by co-immunoprecipitation and immunofluorescence colocalization. This interaction promotes ERK-dependent autophagy, resulting in increased CSCC cell proliferation. Knockdown of FGL2 reduces ERK phosphorylation, autophagy, and proliferation. Co-immunoprecipitation, immunofluorescence, FGL2 knockdown/overexpression, autophagy assays, ERK signaling analysis, in vitro and xenograft models International journal of medical sciences Medium 34975313
2023 FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier (BBB) disruption by inhibiting PI3K/NF-κB-mediated oxidative stress in brain microvascular endothelial cells. PI3K overexpression in FGL2-deleted BMECs re-induces NOX2, iNOS, and NF-κB activation, placing FGL2 upstream of PI3K in this pathway. FGL2-/- mice with LPS-induced maternal inflammation, PI3K inhibitor (LY294002), PI3K lentivirus overexpression in FGL2-deleted BMECs, ROS/NO measurement, tight junction protein expression Frontiers in immunology Medium 37051251
2013 Snf2l (ISWI ATPase chromatin remodeling protein) directly regulates Fgl2 expression in granulosa cells; Snf2l mutant mice fail to induce Fgl2 in response to hCG stimulation, while Snf2l overexpression drives Fgl2 expression. SNF2L also directly interacts with the nuclear receptor co-activator flightless I (FLI-I) by immunoprecipitation. Snf2l exon 6 deletion mouse, hCG stimulation, immunoprecipitation of SNF2L-FLI-I, SNF2L overexpression in granulosa cells Biology of reproduction Medium 23616592
2026 FGL2 in hepatocellular carcinoma cells regulates PD-L1 expression by activating mTORC1 signaling, which phosphorylates and retains TFEB in the cytoplasm, thereby inhibiting lysosome biosynthesis and PD-L1 lysosomal degradation. FGL2 knockout in hepatoma cells reduces PD-L1 expression and synergizes with anti-PD1 therapy. FGL2 knockout in Hepa1-6 cells, mTORC1 signaling analysis, TFEB phosphorylation/nuclear translocation assays, tumor models in Fgl2-/- mice, anti-PD1 combination Cell communication and signaling : CCS Medium 41629991
2025 FGL2 KO in tumor cells impairs CD47 expression through Src and PKCα pathways. Loss of FGL2 in tumor cells induces long-duration brain-resident memory T (TRM) cells that prevent brain tumor recurrence. Reconstitution of CD47 in FGL2-KO tumor cells reverses the anti-tumor protection. CRISPR/Cas9 FGL2 knockout, proteomic analysis of Src/PKCα pathway, CD47 reconstitution, brain immune cell transplant, TRM cell depletion, murine intracranial tumor challenge models Cancer letters Medium 41380903
2013 FGL2 deficiency leads to increased LCMV WE viral titers early post-infection but enhanced DC maturation (CD80, MHC II), increased virus-specific CD8+ and CD4+ T cell IFN-γ production, and higher anti-LCMV antibody titers, demonstrating that FGL2 suppresses adaptive anti-viral immunity by binding to FcγRIIB on APCs. fgl2-/- mice infected with LCMV WE, DC maturation marker flow cytometry, tetramer staining, IFN-γ ELISpot, neutralizing antibody titers PloS one Medium 24146739

Source papers

Stage 0 corpus · 97 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. Journal of immunology (Baltimore, Md. : 1950) 251 9531310
2003 The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis. The Journal of clinical investigation 159 12840059
2008 Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis. Journal of immunology (Baltimore, Md. : 1950) 131 18097026
2019 FGL2 promotes tumor progression in the CNS by suppressing CD103+ dendritic cell differentiation. Nature communications 103 30683885
2008 The FGL2-FcgammaRIIB pathway: a novel mechanism leading to immunosuppression. European journal of immunology 89 18991288
2015 FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas. Journal of the National Cancer Institute 88 25971300
2001 Fgl2 prothrombinase expression in mouse trophoblast and decidua triggers abortion but may be countered by OX-2. Molecular human reproduction 85 11160845
1997 Fulminant hepatic failure in murine hepatitis virus strain 3 infection: tissue-specific expression of a novel fgl2 prothrombinase. Journal of virology 84 9371581
2004 Endothelial induction of fgl2 contributes to thrombosis during acute vascular xenograft rejection. Journal of immunology (Baltimore, Md. : 1950) 79 15100314
1999 The emerging role of immunoregulation of fibrinogen-related procoagulant Fgl2 in the success or spontaneous abortion of early pregnancy in mice and humans. American journal of reproductive immunology (New York, N.Y. : 1989) 69 10429765
2001 Genomic characterization, localization, and functional expression of FGL2, the human gene encoding fibroleukin: a novel human procoagulant. Genomics 66 11170750
2002 Kinetic analysis of a unique direct prothrombinase, fgl2, and identification of a serine residue critical for the prothrombinase activity. Journal of immunology (Baltimore, Md. : 1950) 64 11994472
2014 The Duality of Fgl2 - Secreted Immune Checkpoint Regulator Versus Membrane-Associated Procoagulant: Therapeutic Potential and Implications. International reviews of immunology 61 25259408
2010 The novel immunoregulatory molecule FGL2: a potential biomarker for severity of chronic hepatitis C virus infection. Journal of hepatology 54 20615566
2006 Cytokine-induced hepatic apoptosis is dependent on FGL2/fibroleukin: the role of Sp1/Sp3 and STAT1/PU.1 composite cis elements. Journal of immunology (Baltimore, Md. : 1950) 51 16709865
2014 C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis. Journal of hepatology 50 25200905
2004 The fgl2 prothrombinase/fibroleukin gene is required for lipopolysaccharide-triggered abortions and for normal mouse reproduction. Molecular human reproduction 50 14742694
2012 Downregulation of FGL2/prothrombinase delays HCCLM6 xenograft tumour growth and decreases tumour angiogenesis. Liver international : official journal of the International Association for the Study of the Liver 46 22925132
2003 Th1 cytokines and the prothrombinase fgl2 in stress-triggered and inflammatory abortion. American journal of reproductive immunology (New York, N.Y. : 1989) 45 12852495
2011 FGL2/fibroleukin mediates hepatic reperfusion injury by induction of sinusoidal endothelial cell and hepatocyte apoptosis in mice. Journal of hepatology 44 21756857
1998 Murine hepatitis virus strain 3 induces the macrophage prothrombinase fgl-2 through p38 mitogen-activated protein kinase activation. The Journal of biological chemistry 44 9822700
2015 Deletion of Fibrinogen-like Protein 2 (FGL-2), a Novel CD4+ CD25+ Treg Effector Molecule, Leads to Improved Control of Echinococcus multilocularis Infection in Mice. PLoS neglected tropical diseases 43 25955764
2021 FGL2-wired macrophages secrete CXCL7 to regulate the stem-like functionality of glioma cells. Cancer letters 42 33676940
1999 The nucleocapsid protein of murine hepatitis virus type 3 induces transcription of the novel fgl2 prothrombinase gene. The Journal of biological chemistry 41 10187767
2014 C5a/C5aR pathway is essential for the pathogenesis of murine viral fulminant hepatitis by way of potentiating Fgl2/fibroleukin expression. Hepatology (Baltimore, Md.) 39 24604562
2003 Induction of prothrombinase fgl2 by the nucleocapsid protein of virulent mouse hepatitis virus is dependent on host hepatic nuclear factor-4 alpha. The Journal of biological chemistry 39 12594208
2006 Novel mfgl2 antisense plasmid inhibits murine fgl2 expression and ameliorates murine hepatitis virus type 3-induced fulminant hepatitis in BALB/cJ mice. Human gene therapy 37 16776568
2022 FGL2-MCOLN3-Autophagy Axis-Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis. Cellular and molecular gastroenterology and hepatology 35 35926777
2004 Region-specific expression and secretion of the fibrinogen-related protein, fgl2, by epithelial cells of the hamster epididymis and its role in disposal of defective spermatozoa. The Journal of biological chemistry 34 15377663
1998 Expression of the fgl2 and its protein product (prothrombinase) in tissues during murine hepatitis virus strain-3 (MHV-3) infection. Advances in experimental medicine and biology 33 9782336
2016 C5a/C5aR Pathway Plays a Vital Role in Brain Inflammatory Injury via Initiating Fgl-2 in Intracerebral Hemorrhage. Molecular neurobiology 31 27709492
2010 The FGL2/fibroleukin prothrombinase is involved in alveolar macrophage activation in COPD through the MAPK pathway. Biochemical and biophysical research communications 31 20438701
2011 The prothrombinase activity of FGL2 contributes to the pathogenesis of experimental arthritis. Scandinavian journal of rheumatology 30 21469939
2014 Soluble FGL2, a novel effector molecule of activated hepatic stellate cells, regulates T-cell function in cirrhotic patients with hepatocellular carcinoma. Hepatology international 27 25298849
2012 The significance of microthrombosis and fgl2 in no-reflow phenomenon of rats with acute myocardial ischemia/reperfusion. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 27 22387586
2023 FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells. Nature communications 26 36759517
2012 Characterization of fibrinogen-like protein 2 (FGL2): monomeric FGL2 has enhanced immunosuppressive activity in comparison to oligomeric FGL2. The international journal of biochemistry & cell biology 26 23127799
2013 TNF-α upregulates Fgl2 expression in rat myocardial ischemia/reperfusion injury. Microcirculation (New York, N.Y. : 1994) 25 23432784
2003 Gene transcription of fgl2 in endothelial cells is controlled by Ets-1 and Oct-1 and requires the presence of both Sp1 and Sp3. European journal of biochemistry 25 12752447
2007 Fgl2 deficiency causes neonatal death and cardiac dysfunction during embryonic and postnatal development in mice. Physiological genomics 23 17550996
2013 Targeted deletion of FGL2 leads to increased early viral replication and enhanced adaptive immunity in a murine model of acute viral hepatitis caused by LCMV WE. PloS one 22 24146739
2015 Sodium tanshinone IIA sulfonate ameliorates experimental coronary no-reflow phenomenon through down-regulation of FGL2. Life sciences 20 26482204
2020 FGL2 is positively correlated with enhanced antitumor responses mediated by T cells in lung adenocarcinoma. PeerJ 19 32206449
2007 LPS-induced occult loss in mice requires FGL2. American journal of reproductive immunology (New York, N.Y. : 1989) 19 17997751
2022 Development of allergen-specific IgE in a food-allergy model requires precisely timed B cell stimulation and is inhibited by Fgl2. Cell reports 18 35767958
2018 FGL2 prothrombinase contributes to the early stage of coronary microvascular obstruction through a fibrin-dependent pathway. International journal of cardiology 18 30279004
2013 Soluble FGL2 induced by tumor necrosis factor-α and interferon-γ in CD4+ T cells through MAPK pathway in human renal allograft acute rejection. The Journal of surgical research 18 23664593
2022 miR-146b suppresses LPS-induced M1 macrophage polarization via inhibiting the FGL2-activated NF-κB/MAPK signaling pathway in inflammatory bowel disease. Clinics (Sao Paulo, Brazil) 17 35749999
2019 FGL2 regulates IKK/NF-κB signaling in intestinal epithelial cells and lamina propria dendritic cells to attenuate dextran sulfate sodium-induced colitis. Molecular immunology 17 31743856
2020 Fibrinogen-Like Protein 2 (FGL2) is a Novel Biomarker for Clinical Prediction of Human Breast Cancer. Medical science monitor : international medical journal of experimental and clinical research 16 32716910
2016 Programmed death (PD)-1 attenuates macrophage activation and brain inflammation via regulation of fibrinogen-like protein 2 (Fgl-2) after intracerebral hemorrhage in mice. Immunology letters 16 27717876
2010 The Role of FGL2 in the Pathogenesis and Treatment of Hepatitis C Virus Infection. Rambam Maimonides medical journal 16 23908776
2024 FGL2 promotes tumour growth and attenuates infiltration of activated immune cells in melanoma and ovarian cancer models. Scientific reports 15 38191799
2014 Increased peripheral and local soluble FGL2 in the recovery of renal ischemia reperfusion injury in a porcine kidney auto-transplantation model. Journal of translational medicine 15 24559374
2024 FGL1 and FGL2: emerging regulators of liver health and disease. Biomarker research 14 38816776
2003 Cloning and tissue expression of the tissue prothrombinase Fgl-2 in the Sprague-Dawley rat. Journal of the Society for Gynecologic Investigation 13 12593995
2022 Stat4 rs7574865 polymorphism promotes the occurrence and progression of hepatocellular carcinoma via the Stat4/CYP2E1/FGL2 pathway. Cell death & disease 12 35136014
2018 Soluble Fgl2 restricts autoimmune hepatitis progression via suppressing Tc17 and conventional CD8+ T cell function. The journal of gene medicine 12 29756667
2013 The imitation switch ATPase Snf2l is required for superovulation and regulates Fgl2 in differentiating mouse granulosa cells. Biology of reproduction 12 23616592
2023 FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress. Frontiers in immunology 11 37051251
2022 Targeting FGL2 in glioma immunosuppression and malignant progression. Frontiers in oncology 11 36313679
2016 Two fibrinogen-like proteins, FGL1 and FGL2 are disulfide-linked subunits of oligomers that specifically bind nonviable spermatozoa. The international journal of biochemistry & cell biology 11 27732889
2010 Expression and significance of fgl2 prothrombinase in cardiac microvascular endothelial cells of rats with type 2 diabetes. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 11 21063837
2017 IL-33 protects murine viral fulminant hepatitis by targeting coagulation hallmark protein FGL2/fibroleukin expression. Molecular immunology 10 28494352
2009 Severe acute respiratory syndrome coronavirus nucleocapsid protein does not modulate transcription of the human FGL2 gene. The Journal of general virology 10 19423547
2022 The Fgl2 interaction with Tyrobp promotes the proliferation of cutaneous squamous cell carcinoma by regulating ERK-dependent autophagy. International journal of medical sciences 9 34975313
2019 The FGL2 prothrombinase contributes to the pathological process of experimental pulmonary hypertension. Journal of applied physiology (Bethesda, Md. : 1985) 9 31580221
2024 FGL2172-220 peptides improve the antitumor effect of HCMV-IE1mut vaccine against glioblastoma by modulating immunosuppressive cells in the tumor microenvironment. Oncoimmunology 8 39508842
2018 FGL2 knockdown improves heart function through regulation of TLR9 signaling in the experimental autoimmune myocarditis rats. Immunologic research 8 29128901
2012 Fgl2 prothrombinase is involved in severe acute pancreatitis-associated liver injury. Hepato-gastroenterology 8 22456282
2024 CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB. Nature communications 7 38902261
2019 Author Correction: FGL2 promotes tumor progression in the CNS by suppressing CD103+ dendritic cell differentiation. Nature communications 7 30770835
2003 FGL2 prothrombinase messenger RNA expression in gravid and nongravid human myometrium. American journal of obstetrics and gynecology 7 12712110
2003 Fgl2: link between hepatitis B and SARS? Drug discovery today 6 12946632
2024 FGL2 improves experimental colitis related to gut microbiota structure and bile acid metabolism by regulating macrophage autophagy and apoptosis. Heliyon 5 39104498
2022 Assessment of Fibrinogen-like 2 (FGL2) in Human Chronic Kidney Disease through Transcriptomics Data Analysis. Biomolecules 5 36671474
2022 A homozygous truncating mutation of FGL2 is associated with immune dysregulation. The Journal of allergy and clinical immunology 4 36243222
2012 Inhibitory function of Tregs via soluble FGL2 in chronic hepatitis B. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 4 22886967
2025 Macrophage-derived Fgl2 dampens antitumor immunity through regulation of FcγRIIB+CD8+ T cells in melanoma. JCI insight 3 40125553
2022 Expression of fibrinogen-like protein 2 (Fgl2) on Toll-like receptor 9 (TLR9) expression in autoimmune myelitis. International immunopharmacology 3 36508913
2021 Targeting FGL2, a molecular drug target for glioblastoma, with natural compounds through virtual screening method. Future medicinal chemistry 3 33821685
2020 Fibrinogen-related protein, FGL2, of hamster cauda epididymal fluid: Purification, kinetic analysis of its prothrombinase activity, and its role in segregation of nonviable spermatozoa. Molecular reproduction and development 3 33216420
2024 FGL2/FcγRIIB Signalling Mediates Arterial Shear Stress-Mediated Endothelial Cell Apoptosis: Implications for Coronary Artery Bypass Vein Graft Pathogenesis. International journal of molecular sciences 2 39062880
2024 FGL2: A new target molecule for coagulation and immune regulation in infectious disease. International immunopharmacology 2 39488038
2022 Proteinase-activated Receptor-1 Antagonist Attenuates Brain Injury via Regulation of FGL2 and TLR4 after Intracerebral Hemorrhage in Mice. Neuroscience 2 35182700
2025 Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection. JCI insight 1 40197366
2023 Fibrinogen-Related Protein, Fgl2, of Hamster Cauda Epididymal Fluid: Enzymatic Characterization, and Identification of Fgl2-Binding Proteins and Ligand of Defective Hamster Sperm Organelles. International journal of biochemistry & physiology 1 39135670
2026 Disruption of FGL2 induces TFEB-dependent lysosomal degradation of PD-L1 and enhances the efficacy of anti-PD1 therapy in hepatocellular carcinoma. Cell communication and signaling : CCS 0 41629991
2026 Novel FGL2::PDGFD and TGFBI::PDGFB Fusions Expand the Molecular Spectrum of Dermatofibrosarcoma Protuberans. Genes, chromosomes & cancer 0 41711154
2026 Knockdown of FGL2 ameliorates retinal microvascular endothelial cell injury and oxidative stress in diabetic retinopathy. Microvascular research 0 41794280
2026 Tumor-Derived Exosomes Deliver Membrane-Bound Fgl2 to Activate FcγRIIB-Mediated Immunosuppression in Myeloid-Derived Suppressor Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41875310
2025 Role of fibrinogen-like 2 (FGL2) proteins in implantation: Potential implications and mechanism. Gene 0 39884406
2025 The Maternal-Fetal Interface Fibrin Deposition and Expression of FGL2 in the Placenta of Preeclampsia and Fetal Growth Restriction. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 0 40388520
2025 FGL2-induced metabolic dysregulation in enteric neural crest cells provides insight into Hirschsprung disease pathogenesis. iScience 0 40978140
2025 Fgl2-knockout tumor cells serve as a vaccine inducing long-duration brain-resident memory T cells that reject subsequent intracranial tumor cell challenges. Cancer letters 0 41380903
2025 Hypoxia-preconditioned cardiomyocyte-derived extracellular vesicles alleviate myocardial ischemic injury by reprogramming macrophage polarization via the Fgl2/NF-κB pathway. International immunopharmacology 0 41421228
2025 Association of Serum FGL2 Levels with Asthma Severity and Airway Remodeling. International archives of allergy and immunology 0 41468316