Affinage

GZMB

Granzyme B · UniProt P10144

Round 2 corrected
Length
247 aa
Mass
27.7 kDa
Annotated
2026-04-28
79 papers in source corpus 30 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Granzyme B (GZMB) is a caspase-like serine protease stored with perforin and serglycin in cytotoxic granules of CTLs and NK cells that initiates target cell death through both caspase-dependent and caspase-independent proteolytic pathways. Upon immunological synapse formation, perforin creates transient plasma membrane pores enabling rapid GzmB entry into target cells — facilitated by CI-MPR/IGF2R receptor-mediated uptake — where GzmB directly cleaves Bid to activate the mitochondrial apoptotic pathway and activates caspase-3, which in turn processes caspase-6 and GSDME to trigger pyroptosis (PMID:11081635, PMID:11085743, PMID:8900201, PMID:32188940). GzmB also directly cleaves nuclear substrates DNA-PKcs and NuMA independently of caspases and remodels extracellular matrix by cleaving vitronectin, fibronectin, and laminin (PMID:9586635, PMID:15843372). Cytosolic SERPINB9/PI-9 protects effector lymphocytes from misdirected GzmB, transcription is controlled by synergistic AP-1/CRE promoter elements, and post-transcriptional regulation by miR-27a* and ZFP36L1 tunes GzmB protein output in activated lymphocytes (PMID:8910377, PMID:8219227, PMID:21960590).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1987 High

    Molecular cloning established GZMB as a novel serine protease gene specifically induced in activated human T lymphocytes, resolving the molecular identity of granule-associated cytotoxic protease activity.

    Evidence cDNA cloning, sequencing, and Northern blot in mitogen-stimulated T cell clones

    PMID:2953813

    Open questions at the time
    • enzymatic specificity and substrates unknown
    • no functional cytotoxicity assay performed
  2. 1988 High

    Gene structure analysis revealed GZMB encodes each catalytic triad residue on a separate exon with two unique intron positions, placing it in a distinct serine protease subfamily separate from classical trypsin-like enzymes.

    Evidence genomic cloning and intron–exon mapping

    PMID:3264185

    Open questions at the time
    • substrate specificity not yet determined
    • relationship between gene structure and Asp-ase activity unexplored
  3. 1993 High

    Mapping the transcriptional control of GZMB showed that synergistic action of an AP-1 element and a CRE in the promoter, with critical helical spacing, drives T cell–specific expression in response to TCR and IL-2 receptor signals.

    Evidence promoter-reporter mutagenesis in T cell lines (1990–1993) and transgenic mouse reporter assays (1991)

    PMID:1761544 PMID:2233710 PMID:8219227

    Open questions at the time
    • identity of transcription factor complexes binding the AP-1/CRE composite element not resolved
    • chromatin-level regulation not addressed
  4. 1996 High

    Two key mechanistic questions were answered simultaneously: SERPINB9/PI-9 was identified as a fast-acting cytosolic inhibitor that protects killer cells from self-inflicted GzmB damage, and GzmB was shown to initiate a caspase cascade by activating caspase-3, which then processes caspase-6 to cleave lamins.

    Evidence recombinant serpin–protease kinetics and cytotoxicity inhibition assay; in vitro cleavage cascade reconstitution with caspase mutagenesis

    PMID:8900201 PMID:8910377

    Open questions at the time
    • upstream initiating event in target cells (mitochondrial vs. direct caspase activation) unresolved
    • physiological relevance of PI-9 in vivo not tested
  5. 1998 High

    Discovery that GzmB directly cleaves nuclear substrates DNA-PKcs and NuMA generating fragments distinct from caspase products established a parallel caspase-independent execution pathway.

    Evidence in vitro cleavage assays and immunoblots of CTL-treated target cells

    PMID:9586635

    Open questions at the time
    • relative contribution of caspase-dependent vs. -independent pathways to cell death in vivo unknown
    • full substrate repertoire not defined
  6. 2000 High

    Two foundational discoveries resolved GzmB's upstream activation mechanism and entry route: direct Bid cleavage was established as the essential initiating step for mitochondrial apoptosis, and CI-MPR/IGF2R was identified as the cell-surface receptor mediating GzmB uptake.

    Evidence Bid cleavage-site and BH3 mutants with Bcl-2 epistasis; CI-MPR blocking antibodies, CI-MPR-deficient cells, and in vivo allograft rejection

    PMID:11081635 PMID:11085743

    Open questions at the time
    • perforin's mechanism of cytosolic delivery versus CI-MPR endosomal uptake debated
    • structural basis of GzmB–CI-MPR interaction unknown
  7. 2001 High

    Rab27a was identified as essential for late-stage exocytosis of GzmB-containing cytotoxic granules, linking granule trafficking machinery to killer cell function.

    Evidence Rab27a-deficient (ashen) mouse CTLs with cytotoxicity and secretion assays

    PMID:11266473

    Open questions at the time
    • downstream effectors of Rab27a at the granule membrane not identified
    • whether Rab27a acts identically in human CTLs untested
  8. 2002 High

    Biochemical isolation of GzmB–serglycin–perforin macromolecular complexes from granules showed that GzmB is secreted exclusively in these complexes and delivered to the cytosol by perforin without producing stable plasma membrane pores.

    Evidence granule biochemistry with size-exclusion chromatography, ELISA, and membrane permeabilization assays

    PMID:11911826

    Open questions at the time
    • stoichiometry of serglycin complex not determined
    • mechanism by which perforin releases GzmB from serglycin in the cytosol unclear
  9. 2005 High

    Demonstration that GzmB cleaves ECM proteins vitronectin, fibronectin, and laminin revealed a perforin-independent extracellular function in ECM remodeling, cell detachment, and anoikis.

    Evidence in vitro cleavage of purified ECM substrates, cell detachment assays, migration/invasion assays

    PMID:15843372

    Open questions at the time
    • in vivo relevance of ECM cleavage in tumor surveillance or tissue injury not established
    • full spectrum of extracellular substrates unknown
  10. 2013 High

    Real-time imaging resolved the kinetics of GzmB delivery: perforin forms transient pores lasting <80 seconds at the synapse, sufficient to deliver lethal GzmB amounts that trigger caspase activation within 2 minutes; separately, hypoxia-induced autophagy in target cells was shown to degrade internalized GzmB in autophagosomes, representing a tumor immune evasion mechanism.

    Evidence time-lapse microscopy of human CTL synapses with calcium and caspase reporters; BECN1 knockdown with NK cytotoxicity assays and in vivo tumor models

    PMID:23377437 PMID:24101526 PMID:24248158

    Open questions at the time
    • molecular mechanism of GzmB recognition by autophagosomes unresolved
    • whether autophagy-mediated GzmB degradation occurs broadly across tumor types untested
  11. 2011 High

    Post-transcriptional regulation of GZMB by miR-27a* was established: miR-27a* directly binds the GzmB 3′UTR, suppresses protein expression, and reduces NK cytotoxicity in vitro and tumor control in vivo.

    Evidence 3′UTR luciferase reporter, miRNA knockdown in NK cells, tumor xenograft model

    PMID:21960590

    Open questions at the time
    • whether miR-27a* is regulated during physiological immune responses unknown
    • combinatorial miRNA regulation of GzmB not systematically addressed
  12. 2020 High

    GzmB was shown to directly cleave GSDME at the caspase-3 cleavage site, converting target cell apoptosis to pyroptosis; this GzmB→GSDME axis amplifies anti-tumor immunity by enhancing macrophage phagocytosis and lymphocyte infiltration, but also drives CAR T cell-associated cytokine release syndrome via secondary GSDMD activation in macrophages.

    Evidence in vitro GzmB cleavage of recombinant GSDME, GSDME-KO mice, perforin-KO mice, CAR T cell CRS model with macrophage depletion

    PMID:31953257 PMID:32188940

    Open questions at the time
    • relative contribution of direct GSDME cleavage vs. caspase-3-mediated GSDME cleavage during physiological killing not quantified
    • structural basis of GzmB–GSDME recognition unknown
  13. 2024 High

    CRISPR knockout of GZMB in primary human CD8+ T cells demonstrated that GzmB is required not only for cytotoxicity but also for CD8+ T cell-mediated immune suppression, broadening its functional role beyond target cell killing.

    Evidence CRISPR-Cas9 RNP KO in primary human CD8+ T cells with in vitro suppression assay

    PMID:38607279

    Open questions at the time
    • mechanism by which GzmB mediates suppression (target cell apoptosis vs. cytokine processing) unresolved
    • in vivo confirmation in regulatory CD8+ T cell context lacking
  14. 2025 Medium

    ZFP36L1 was identified as the post-transcriptional brake that keeps GzmB protein low despite abundant mRNA in tumor-infiltrating CD4+ cytotoxic T cells; checkpoint blockade relieves this brake, and Zfp36l1 deletion is sufficient to unleash GzmB protein and promote tumor control.

    Evidence Zfp36l1 constitutive expression and genetic deletion in CD4+ T cells with anti-CTLA-4 treatment and tumor growth assays (preprint)

    Open questions at the time
    • direct RNA-binding site of ZFP36L1 on GZMB mRNA not mapped
    • pending peer review
    • whether this mechanism operates in CD8+ T cells untested
  15. 2026 High

    SDC1 (syndecan-1) was identified as a direct GzmB substrate whose cleavage at Val-225/Asp-228 blocks autophagosome maturation by displacing TGM2 from lysosomes, linking GzmB's proteolytic activity to suppression of cytoprotective autophagy in glioblastoma.

    Evidence in vitro cleavage site mapping, uncleavable SDC1 mutant rescue, TGM2 lysosome localization, xenograft radiosensitization model

    PMID:41378763

    Open questions at the time
    • whether SDC1 cleavage by GzmB occurs in non-GBM contexts unknown
    • structural mechanism of TGM2 displacement not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the complete in vivo substrate repertoire of GzmB, the structural basis of substrate selectivity, the precise mechanism by which perforin releases GzmB from serglycin complexes into the target cytosol, and the relative contributions of the Bid/mitochondrial, direct caspase, and GSDME pyroptotic pathways across different physiological and pathological contexts.
  • comprehensive in vivo substrate identification lacking
  • no crystal structure of GzmB–substrate complex available
  • perforin–serglycin dissociation mechanism unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 5
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005576 extracellular region 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-9612973 Autophagy 3 R-HSA-1474244 Extracellular matrix organization 1
Partners
BIDCASP3GSDMEIGF2RPRF1RAB27ASDC1SERPINB9
Complex memberships
GzmB–serglycin–perforin granule complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 GZMB (clone 1-3E) encodes a 247-residue serine protease induced in mitogen-stimulated human T lymphocytes; its mRNA is expressed specifically in T lymphocyte clones and is most closely related (68% homology) to murine cytotoxic T lymphocyte protease CCPI. cDNA cloning and sequencing, Northern blot expression analysis Journal of immunology High 2953813
1988 The GZMB gene (CCPII) shares a gene organization with other serine protease genes in which each active-site residue is on a separate exon; two introns occur at unique positions — one within the activation dipeptide and one interrupting the invariant core region near the active-site Asp — defining GZMB as a new subfamily of serine protease genes. Genomic cloning, sequencing, and gene structure analysis Biochemistry High 3264185
1990 Transcriptional activation of CSP-B/GZMB in T lymphocytes requires synergistic action of TPA and cAMP (bt2cAMP); neither agent alone activates transcription. Upon activation, a DNase I-hypersensitive site forms upstream from the gene, and the region −615 to −63 functions as an orientation-specific upstream promoter element. Transient transfection of promoter-reporter constructs, DNase I hypersensitivity assay, Northern blot Molecular and cellular biology High 2233710
1991 The 5′-flanking region of the human GZMB (CSP-B/CGL-1) gene is sufficient to drive expression specifically in activated T lymphocytes in vivo; expression is induced by ConA or IL-2 (but not in resting cells), responding to signals from both the TCR and the IL-2 receptor. Transgenic mouse reporter assay (human growth hormone driven by CSP-B promoter) The Journal of biological chemistry High 1761544
1993 A consensus AP-1 element and a consensus CRE located 5′ to the GZMB transcriptional start site both are required and synergize for transcriptional activation; the AP-1 site is dominant (replacement with a second AP-1 retains activity, but replacement with a CRE abolishes it); helical spacing between the two elements is critical, suggesting cooperative DNA-bound factor interactions. Transient transfection of promoter constructs with point mutations and deletions in PEER T cells Blood High 8219227
1996 Proteinase inhibitor 9 (PI-9/SERPINB9) forms an SDS-resistant covalent complex with granzyme B with a second-order rate constant of 1.7×10⁶ M⁻¹s⁻¹, completely abrogates granzyme B– and perforin-mediated cytotoxicity in vitro, and is a cytosolic (not secreted) protein present in a separate subcellular compartment from granzyme B in NK cells — functioning as an endogenous inhibitor that protects cytotoxic lymphocytes from misdirected granzyme B. Recombinant protein production, serpin-protease complex assay, kinetic analysis, cytotoxicity assay, subcellular fractionation, immunofluorescence The Journal of biological chemistry High 8910377
1996 Granzyme B can process pro-Mch2alpha (caspase-6) and pro-Mch6 (caspase-14/caspase-9 homolog), but cleavage of pro-Mch2alpha by granzyme B alone is insufficient; granzyme B must first activate CPP32 (caspase-3), which then processes pro-Mch2alpha to generate active lamin-cleaving enzyme — establishing a protease cascade: granzyme B → caspase-3 → caspase-6/lamin cleavage. In vitro cleavage assays with recombinant proteins, site-directed mutagenesis, cell-free extract reconstitution The Journal of biological chemistry High 8900201
1998 Granzyme B directly and efficiently cleaves downstream caspase substrates DNA-PKcs and NuMA in vitro and in vivo, generating cleavage fragments distinct from those produced by caspases, demonstrating a caspase-independent direct proteolytic execution pathway. In vitro cleavage assays, cell-free apoptosis system, immunoblot of cleavage products in CTL-treated cells Immunity High 9586635
2000 Granzyme B initiates apoptosis through the mitochondrial pathway by directly cleaving Bid; this Bid cleavage occurs upstream of and independently of mitochondrial Bcl-2, is not delayed by caspase inhibition, and is required (mutation of GrB cleavage site in Bid abolishes apoptosis restoration) — placing direct Bid cleavage as the essential upstream step in GrB-mediated mitochondrial pathway activation. Bcl-2-overexpressing cell lines, Bid mutants (cleavage site and BH3 domain mutations), granzyme B treatment with caspase inhibitors, flow cytometry of mitochondrial membrane potential The Journal of experimental medicine High 11085743
2000 The cation-independent mannose 6-phosphate receptor (CI-MPR/IGF2R) is identified as a cell-surface receptor for granzyme B; blocking this interaction prevents GrB binding, uptake, and apoptosis induction; CI-MPR expression is required for CTL-mediated apoptosis in vitro and for allogeneic cell rejection in vivo. Receptor blocking with antibodies/ligands, CI-MPR-deficient cells, in vitro cytotoxicity assay, in vivo allograft rejection model Cell High 11081635
2001 Rab27a, which colocalizes with granzyme B-positive secretory granules, is required for a late step in granule exocytosis; Rab27a-deficient (ashen) CTLs have normal perforin and granzyme A/B levels and normal granule polarization, but show >90% reduction in granule-mediated cytotoxicity and drastically defective rapid anti-CD3-induced granule secretion. Rab27a-deficient ashen mouse CTLs, granule polarization assay, cytotoxicity assay, granzyme secretion measurement, immunofluorescence colocalization The Journal of cell biology High 11266473
2002 Granzyme B and perforin co-exist as multimeric complexes with the proteoglycan serglycin in cytotoxic granules, and cytotoxic cells secrete exclusively macromolecular GrB-serglycin complexes; perforin mediates cytosolic delivery of these macromolecular GrB-serglycin complexes without producing detectable plasma membrane pores. Granule biochemistry, size-exclusion chromatography, ELISA, electron microscopy, membrane permeabilization assays Immunity High 11911826
2003 Granzyme B functions as a caspase-like serine protease released by cytotoxic lymphocytes; PI-9 (SERPINB9) regulates its function in lymphocytes; granzyme B can enter and traffic within target cells and triggers cell death through Bid cleavage and caspase activation. Review synthesizing biochemical and cell biological evidence from multiple primary studies Current opinion in immunology High 14499262
2004 Granzyme B is differentially expressed in human lymphocyte subsets: most CD56+CD8− NK cells and ~50% of CD8+ T cells co-express granzymes A and B; activation with ConA/IL-2 or anti-CD3/CD46 strongly induces granzyme B (but not A) in both CD8+ and CD4+ T cells; granzyme B-expressing CD4+ Tr1 cells kill target cells in a perforin-dependent, MHC/TCR-independent manner. Flow cytometry (intracellular staining), activation assays, perforin-dependent killing assay Blood High 15238416
2005 Human granzyme B cleaves extracellular matrix proteins vitronectin (after an RGD motif), fibronectin, and laminin, causing cell detachment and anoikis of endothelial cells, and inhibiting tumor cell spreading, migration, and invasion — revealing a perforin-independent ECM remodeling activity of secreted granzyme B. In vitro cleavage assays with purified ECM proteins, cell detachment and anoikis assays, migration/invasion assays, cleavage site mapping The Journal of biological chemistry High 15843372
2009 Granzyme B-induced apoptosis of ectromelia-infected target cells is totally dependent on caspase-3/-7 (not Bid/Bak/Bax pathway); ectromelia virus can partially block GzmB-induced apoptosis when caspase-3/-7 is the only available pathway, but inhibition of viral replication in vitro was significantly reduced only in caspase-3/-7-deficient cells — establishing caspase-3/-7 as the critical pathway for GzmB-mediated viral control. Ex vivo immune Tc cells from GzmA-KO and GzmAxB-DKO mice, caspase-3/-7-deficient and Bid/Bak/Bax-deficient target cells, viral titer measurement, apoptosis assays PloS one High 19838298
2011 Human miR-27a* is a negative regulator of NK cell cytotoxicity by directly binding the 3′UTR of both Prf1 and GzmB mRNAs and down-regulating their expression in both resting and activated NK cells; knockdown of miR-27a* in NK cells dramatically increases cytotoxicity in vitro and decreases tumor growth in a xenograft model. 3′UTR luciferase reporter assay, miRNA overexpression/knockdown, NK cell cytotoxicity assay, tumor xenograft model Blood High 21960590
2013 Hypoxia-induced autophagy in breast cancer cells causes selective degradation of NK-derived granzyme B in autophagosomes, blocking NK-mediated target cell apoptosis; inhibition of autophagy by targeting BECN1 restores granzyme B levels in hypoxic cells and induces tumor regression in vivo by facilitating NK killing. Autophagy inhibition (BECN1 knockdown), GrB immunofluorescence/colocalization with autophagosomes, NK cytotoxicity assay, in vivo tumor regression model Proceedings of the National Academy of Sciences High 24101526
2013 Hypoxia-induced autophagy impairs breast cancer cell susceptibility to NK-mediated lysis by selectively degrading GZMB in autophagosomes of hypoxic cells, thereby blocking NK-mediated apoptosis; targeting autophagy reverses this and promotes tumor regression in vivo. Autophagy activation/inhibition, GZMB immunofluorescence, autophagosome-lysosome colocalization, NK cytotoxicity assay, in vivo xenograft Autophagy High 24248158
2013 Perforin forms transient pores on the target cell plasma membrane within 30 seconds of cytotoxic lymphocyte recognition, allowing rapid diffusion of extracellular granzymes into the synaptic cleft and entry into target cells; pore repair begins within 20 seconds and is complete within 80 seconds, yet this brief window is sufficient to deliver lethal granzyme B amounts triggering caspase-dependent apoptosis within 2 minutes. Time-lapse microscopy of human primary CTLs at immunological synapses, calcium flux assays, pore kinetics, caspase activity monitoring Blood High 23377437
2015 miR-378 (but not miR-27a* or miR-30e) suppresses GzmB expression in NK cells during dengue virus infection; overexpression of miR-378 in DENV-infected mice inhibited GzmB expression and promoted DENV replication, establishing miR-378 as a critical regulator of GzmB-mediated NK cell control of viral infection. miRNA agomir overexpression in vivo, GzmB expression measurement (flow cytometry), viral titer measurement in infected mice Cellular & molecular immunology Medium 26166761
2017 QPY/RAH polymorphism (rs8192917; Q48R) in the GZMB gene influences NK cell cytotoxicity; R48-GzmB accumulates to similar levels as Q48-GzmB in activated NK cells but NK cell cytotoxicity is significantly influenced by this non-synonymous SNP, suggesting the R48 variant alters functional activity rather than protein stability. Genotyping of NK cell donors, NK cytotoxicity assay (51Cr release), GzmB protein quantification by flow cytometry/ELISA, degranulation assay Immunogenetics Medium 28653095
2020 Granzyme B directly cleaves GSDME (Gasdermin E) at the same site as caspase-3, converting apoptosis to pyroptosis in target cells; GSDME-mediated pyroptosis triggered by killer cell granzyme B enhances anti-tumor immunity through increased phagocytosis by macrophages and augmented NK and CD8+ T cell tumor infiltration; uncleavable or pore-defective GSDME abolishes tumor suppression. In vitro GrB cleavage assay with recombinant GSDME, GSDME knockout/knockin mice, perforin-deficient mice, lymphocyte depletion, tumor growth assays, macrophage phagocytosis assay Nature High 32188940
2020 CAR T cell-released granzyme B cleaves GSDME in target (B leukemic) cells, activating caspase 3-dependent pyroptosis; pyroptosis-released factors then activate caspase 1 for GSDMD cleavage in macrophages, triggering cytokine release syndrome (CRS); GSDME knockout or macrophage depletion eliminates CRS in mouse models. GSDME knockout target cells, macrophage depletion, caspase 1 inhibition, CAR T cell co-culture, CRS mouse model, GrB quantification Science immunology High 31953257
2021 The transcription factor SP1 represses GZMB expression in lung cancer cells; inhibiting SP1 (via AuNPs-siRNA-SP1) upregulates GZMB, promotes G2/M arrest, increases DNA double-strand breaks, and enhances radiosensitivity both in vitro and in vivo. SP1 siRNA knockdown, Western blot, RT-qPCR, colony formation assay, flow cytometry cell cycle and apoptosis, immunofluorescence (γH2AX), xenograft tumor model Translational oncology Medium 34517158
2022 Tcf-1B expression in CD8+ T cells prohibits acquisition of a GzmB-high state during effector differentiation, protecting TCR-engineered T cells from activation-induced cell death (fratricidal GzmB-mediated apoptosis) and promoting stem cell-like persistence. Constitutive Tcf-1B expression in CD8+ T cells, flow cytometry of GzmB expression, apoptosis assays, in vitro anti-tumor activity, in vivo xenograft model Cancer immunology, immunotherapy Medium 35460379
2023 GZMB activates the caspase-3–GSDME (Gasdermin E) pyroptosis pathway in rheumatoid arthritis synovial cells; GZMB silencing reduces caspase-3 and GSDME activation, decreases pyroptosis markers (LDH, IL-1β, IL-18), and reduces cell proliferation in HFLS-RA and MH7A cells. GZMB siRNA knockdown, CCK8 and EDU proliferation assays, LDH assay, ELISA (IL-1β, IL-18), Western blot of GZMB/caspase-3/GSDME Molecular immunology Medium 37531918
2024 GZMB inhibition (by SerpinA3N) in diabetic mice reduces endoplasmic reticulum stress (PERK/eIF2α pathway) and pyroptosis (NLRP3/caspase-1/GSDMD-N/IL-1β/IL-18) in hippocampal oligodendrocytes, reduces demyelination (restores MBP and CNPase expression), and ameliorates cognitive dysfunction — establishing GZMB as a promoter of oligodendrocyte ER stress and pyroptosis leading to demyelination. Streptozotocin diabetic mouse model, SerpinA3N (GZMB inhibitor) treatment, Morris water maze, immunofluorescence, Luxol Fast Blue staining, electron microscopy, Western blot Free radical biology & medicine Medium 39326683
2024 CRISPR-Cas9 knockout of GZMB (alongside PRF1, LYST, or IFNγ) in primary human CD8+ T cells significantly diminishes their in vitro immune suppressive ability, establishing that GZMB is required for CD8+ T cell-mediated immune suppression. CRISPR-Cas9 RNP knockout in primary human CD8+ T cells, RT-qPCR and flow cytometry confirmation of KO, in vitro T cell suppression assay Journal of immunology High 38607279
2026 NK cell-derived GZMB suppresses glioblastoma radioresistance by directly cleaving SDC1 (syndecan-1) at valine-225 and aspartate-228 sites, blocking autophagosome-lysosome fusion; SDC1 cleavage disrupts TGM2 localization on the lysosome surface (a key LC3 recognizer), impairing autophagosome maturation and thereby radiosensitizing GBM cells. Co-culture NK/GBM experiments, GZMB activity inhibition, exogenous recombinant GZMB, in vitro cleavage assay identifying SDC1 cleavage sites, uncleavable SDC1 mutant rescue experiment, TGM2 lysosome localization assay, xenograft model, clinical data correlation Autophagy High 41378763
2025 In CD4+ cytotoxic T cells (TCTX) in untreated tumors, Gzmb mRNA is abundant but Granzyme B protein is limited (poised state); anti-CTLA-4 or anti-LAG-3+anti-PD-1 treatment removes this post-transcriptional block by repressing the RNA-binding protein Zfp36l1; constitutive Zfp36l1 expression abrogates anti-CTLA-4 effects on GzmB protein, while deletion of Zfp36l1 and its paralog Zfp36 triggers GzmB protein production and promotes tumor control. Zfp36l1 constitutive expression and genetic deletion, anti-CTLA-4/anti-LAG-3+PD-1 treatment, GzmB protein vs. mRNA quantification, tumor growth assays bioRxivpreprint Medium
2025 IFNγ is stored within GzmB+ cytotoxic granules in activated mouse and human CD8+ T cells ('lytic IFNγ') and is co-secreted with GzmB at the immunological synapse; Munc13-4-deficient T cells show impaired both cytotoxic granule and early IFNγ release at the synapse, linking GzmB granule exocytosis machinery to IFNγ secretion. Super-resolution imaging, Munc13-4 KO T cells, time-lapse microscopy of immunological synapses, granule-IFNγ colocalization, SMAP isolation bioRxivpreprint Medium
2025 Granzyme-targeting quenched activity-based probe Cy5-IEPCya(Ph)P-QSY21 reacts rapidly with GzmB at substoichiometric concentrations and enables selective labeling of the active enzyme in complex proteomes; in vivo fluorescence signals correlate with GzmB expression/activity and CD8+ cell density in tumor tissues. Activity-based probe synthesis, in vitro selectivity assays, in vivo optical imaging in immunotherapy-treated mice, ex vivo correlation with GzmB expression bioRxivpreprint Medium
2025 Supramolecular attack particles (SMAPs) enriched from NK-92 cell cultures contain GZMB and PRF1 as core cytotoxic components; Ca2+-stabilized SMAPs trigger caspase-3-dependent apoptosis in tumor cell lines in a dose-dependent manner, and restrain tumor growth in NSG mice bearing B16F10 melanoma and PANC-1 pancreatic cancer. Serial size-exclusion chromatography SMAP isolation, proteomics, nano flow cytometry, TEM, TIRFM, caspase-3 apoptosis assay, NSG mouse xenograft models bioRxivpreprint Medium

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Caspases: the executioners of apoptosis. The Biochemical journal 3881 9337844
1998 Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 2970 9727491
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
2020 Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 1315 32188940
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
1998 Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Molecular cell 954 9651578
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2020 Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Science immunology 469 31953257
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2004 Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 391 15238416
2005 XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. The EMBO journal 320 15650747
2010 Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. The New England journal of medicine 304 20410501
2000 Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. The Journal of experimental medicine 300 11085743
2000 Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 295 11081635
2010 Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. The Journal of cell biology 290 20530211
2013 Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proceedings of the National Academy of Sciences of the United States of America 277 24101526
1998 Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity 272 9586635
1996 The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32. The Journal of biological chemistry 268 8900201
2017 Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response. Cancer research 266 28461564
1996 A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes. The Journal of biological chemistry 254 8910377
2013 Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proceedings of the National Academy of Sciences of the United States of America 235 23898208
1987 Induction of mRNA for a serine protease and a beta-thromboglobulin-like protein in mitogen-stimulated human leukocytes. Journal of immunology (Baltimore, Md. : 1950) 229 2953813
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
2002 CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 219 12200377
2005 Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. The Journal of biological chemistry 216 15843372
2003 Granzyme B: pro-apoptotic, antiviral and antitumor functions. Current opinion in immunology 214 14499262
2003 Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nature immunology 210 12524539
2002 Cytotoxic cell granule-mediated apoptosis: perforin delivers granzyme B-serglycin complexes into target cells without plasma membrane pore formation. Immunity 208 11911826
2013 Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood 207 23377437
2001 Defective granule exocytosis in Rab27a-deficient lymphocytes from Ashen mice. The Journal of cell biology 206 11266473
2023 Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB-CD8+ memory T cells and accumulation of type 2 memory T cells. Immunity 121 37963457
2011 Human microRNA-27a* targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity. Blood 116 21960590
2001 Production of delayed death and neoplastic transformation in CGL1 cells by radiation-induced bystander effects. Radiation research 80 11500134
2013 Autophagic degradation of GZMB/granzyme B: a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis. Autophagy 71 24248158
2003 Re-evaluation of the RBE of 29 kV x-rays (mammography x-rays) relative to 220 kV x-rays using neoplastic transformation of human CGL1-hybrid cells. Radiation and environmental biophysics 46 14551783
1988 Organization of two genes encoding cytotoxic T lymphocyte-specific serine proteases CCPI and CCPII. Biochemistry 46 3264185
2015 Suppressed expression of miR-378 targeting gzmb in NK cells is required to control dengue virus infection. Cellular & molecular immunology 37 26166761
1991 The 5'-flanking region of the human CGL-1/granzyme B gene targets expression of a reporter gene to activated T-lymphocytes in transgenic mice. The Journal of biological chemistry 37 1761544
1993 Consensus AP-1 and CRE motifs upstream from the human cytotoxic serine protease B (CSP-B/CGL-1) gene synergize to activate transcription. Blood 35 8219227
1990 Transcriptional activation of the human cytotoxic serine protease gene CSP-B in T lymphocytes. Molecular and cellular biology 35 2233710
2016 A rare subset of skin-tropic regulatory T cells expressing Il10/Gzmb inhibits the cutaneous immune response. Scientific reports 31 27756896
2021 Long Non-coding RNA LINC02474 Affects Metastasis and Apoptosis of Colorectal Cancer by Inhibiting the Expression of GZMB. Frontiers in oncology 27 33898319
2018 The miRNA 361-3p, a Regulator of GZMB and TNF Is Associated With Therapeutic Failure and Longer Time Healing of Cutaneous Leishmaniasis Caused by L. (viannia) braziliensis. Frontiers in immunology 27 30487794
2018 RETRACTED: GZMB gene silencing confers protection against synovial tissue hyperplasia and articular cartilage tissue injury in rheumatoid arthritis through the MAPK signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 29669300
2018 Genetic polymorphisms of GZMB and vitiligo: A genetic association study based on Chinese Han population. Scientific reports 22 30158536
2017 Fine-Mapping and Analysis of Cgl1, a Gene Conferring Glossy Trait in Cabbage (Brassica oleracea L. var. capitata). Frontiers in plant science 21 28265282
2022 Decreased GZMB, NRP1, ITPR1, and SERPINB9 Transcripts Lead to Reduced Regulatory T Cells Suppressive Capacity in Generalized Vitiligo Patients. Journal of immunology research 19 36157881
2013 Risk of generalized vitiligo is associated with the common 55R-94A-247H variant haplotype of GZMB (encoding granzyme B). The Journal of investigative dermatology 16 23321921
2023 Exploring the molecular mechanisms of the involvement of GZMB-Caspase-3-GSDME pathway in the progression of rheumatoid arthritis. Molecular immunology 15 37531918
2021 Association of GZMB polymorphisms and susceptibility to non-segmental vitiligo in a Korean population. Scientific reports 15 33431938
2005 A radiation-induced acute apoptosis involving TP53 and BAX precedes the delayed apoptosis and neoplastic transformation of CGL1 human hybrid cells. Radiation research 15 15913393
2021 Radiosensitizing effect of gold nanoparticle loaded with small interfering RNA-SP1 on lung cancer: AuNPs-si-SP1 regulates GZMB for radiosensitivity. Translational oncology 13 34517158
2017 The CGL1 (HeLa × Normal Skin Fibroblast) Human Hybrid Cell Line: A History of Ionizing Radiation Induced Effects on Neoplastic Transformation and Novel Future Directions in SNOLAB. Radiation research 13 28873027
2000 Loss of chromosome 14 increases the radiosensitivity of CGL1 human hybrid cells but lowers their susceptibility to radiation-induced neoplastic transformation. Mutagenesis 13 10792009
2017 QPY/RAH haplotypes of the GZMB gene are associated with natural killer cell cytotoxicity. Immunogenetics 12 28653095
2019 Transcriptomic profiling of gamma ray induced mutants from the CGL1 human hybrid cell system reveals novel insights into the mechanisms of radiation-induced carcinogenesis. Free radical biology & medicine 11 31580949
2009 Caspase-dependent inhibition of mousepox replication by gzmB. PloS one 11 19838298
2024 Disruption of IFNγ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 10 38607279
2022 Identification of Radiation-Induced miRNA Biomarkers Using the CGL1 Cell Model System. Bioengineering (Basel, Switzerland) 9 35621492
2022 Tcf-1 protects anti-tumor TCR-engineered CD8+ T-cells from GzmB mediated self-destruction. Cancer immunology, immunotherapy : CII 8 35460379
2023 Genomic Loss and Epigenetic Silencing of the FOSL1 Tumor Suppressor Gene in Radiation-induced Neoplastic Transformation of Human CGL1 Cells Alters the Tumorigenic Phenotype In Vitro and In Vivo. Radiation research 7 37141110
2025 Targeting PD-1 and CD85j can restore intratumoral CD4+ GzmB+ T-cell functions to combat MHC-II-expressing tumors. Journal for immunotherapy of cancer 6 40169283
2024 Characteristics and functions of an atypical inflammation-associated GZMK+GZMB+CD8+ T subset in people living with HIV-1. Molecular immunology 6 39053388
2021 MiR-518a-5p Targets GZMB to Extenuate Vascular Endothelial Cell Injury Induced by Hypoxia-Reoxygenation and Thereby Improves Myocardial Ischemia. International heart journal 6 33994508
2024 Inhibition of GZMB activity ameliorates cognitive dysfunction by reducing demyelination in diabetic mice. Free radical biology & medicine 5 39326683
2021 Identification of CD56dim subpopulation marked with high expression of GZMB/PRF1/PI-9 in CD56+ interferon-α-induced dendritic cells. Genes to cells : devoted to molecular & cellular mechanisms 5 33662167
2025 Single-cell profiling reveals immunoregulation of artemisinin on CD8+GZMB+ T cells via JAK2-STAT3 in malaria-infected mice. Innovation (Cambridge (Mass.)) 3 40979296
2023 A common genetic variation in GZMB may associate with cancer risk in patients with Lynch syndrome. Frontiers in oncology 3 36890824
2022 Expression of the GZMB Gene Polymorphism, SNP rs8192917, in 990 Han Chinese Patients with Postoperative Keloids. Medical science monitor : international medical journal of experimental and clinical research 3 35733327
2022 Tuberculosis infection related hemophagocytic lymphohistiocytosis diagnosed in patient with GZMB mutation: A case report and literature review. Medicine 3 36107603
2022 Coprinopsis cinerea Galectin CGL1 Induces Apoptosis and Inhibits Tumor Growth in Colorectal Cancer Cells. International journal of molecular sciences 3 36613681
2025 CXCL8 and GZMB genes promote cartilaginous and synovial lesion formation via NF-κB and MAPK signaling pathways in Kaschin-Beck disease. Biochimica et biophysica acta. Molecular basis of disease 2 40414318
2024 The Role of Natural Background Radiation in Maintaining Genomic Stability in the CGL1 Human Hybrid Model System. Radiation research 2 39134062
2022 Influences of miR-378a-3p on the Pathogenesis of Allergic Rhinitis via GzmB-Mediated Inflammatory Reaction. Evidence-based complementary and alternative medicine : eCAM 2 36072399
2024 Immune Rejection Mediated by prf1 and gzmb Affects the Colonization of Fat Greenling (Hexagrammos otakii) Spermatogonia in Heterotransplantation. International journal of molecular sciences 1 38791196
2026 NK cell-derived GZMB (granzyme B) suppresses glioblastoma radioresistance by blocking SDC1-mediated autophagosome maturation. Autophagy 0 41378763
2026 The transcription factor ZNF683 marks an exhaustion-like GZMB+CD8+ T cell in sepsis. Frontiers in immunology 0 41869345
2025 SLC4A10 impedes atherosclerosis by diminishing IFN-γ/GZMB levels of CD8+ T cells via the MAPK pathway. Frontiers in immunology 0 40510365
2023 Mannose oligosaccharide recognition of CGL1, a mannose-specific lectin containing DM9 motifs from Crassostrea gigas, revealed by X-ray crystallographic analysis. Journal of biochemistry 0 37793172