Affinage

CASP6

Caspase-6 · UniProt P55212

Length
293 aa
Mass
33.3 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASP6 is an executioner cysteine protease that cleaves a distinct repertoire of protein substrates during apoptosis and fulfills non-enzymatic scaffold functions in innate immune signaling. As the sole apoptotic laminase, CASP6 cleaves lamin A/C at the VEID↓NG site to drive nuclear envelope disassembly and chromatin condensation, and it processes diverse substrates including tau (at D13), APP, huntingtin (at D586), p97/VCP, SATB1, CBP, RIPK1, IRAK-M, DJ-1, AP-2α, and UFD2, linking it to neurodegeneration, ubiquitin-proteasome disruption, and inflammatory signaling (PMID:8710882, PMID:11953316, PMID:15356202, PMID:10438520, PMID:20427671, PMID:22858542, PMID:21098228). CASP6 is activated by upstream caspase-1 (via the NLRP1 inflammasome), caspase-9, or through self-processing at D179/D193, and its activity is negatively regulated by AMPK/ARK5-mediated phosphorylation at Ser257, which causes substrate-binding groove misalignment as revealed by crystal structures, and by thioredoxin-1 redox state; it is a direct p53 transcriptional target induced through intronic p53 response elements (PMID:25744023, PMID:22483120, PMID:22433863, PMID:30769159, PMID:12089322). Independent of its catalytic activity, CASP6 facilitates RIPK3–ZBP1 PANoptosome assembly through RHIM-dependent binding during influenza A virus infection, demonstrating a scaffold function in innate immunity (PMID:32298652).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Identification of CASP6 as a novel cysteine protease capable of cleaving PARP and inducing apoptosis established it as a member of the executioner caspase family.

    Evidence Recombinant protein expression, fluorogenic peptide cleavage, PARP cleavage, and baculovirus overexpression in Sf9 cells

    PMID:7796396

    Open questions at the time
    • Physiological substrates unknown
    • Relationship to other caspases not established
    • Activation mechanism not defined
  2. 1996 High

    Discovery that CASP6 is the specific apoptotic laminase — cleaving lamin A at VEID↓NG while caspase-3 cannot — defined its unique substrate specificity and explained how nuclear lamina disassembly is executed during apoptosis.

    Evidence In vitro cleavage assays with recombinant caspases, cell-free apoptosis extracts, granzyme B processing, epistasis with Bcl-2/CrmA

    PMID:8663580 PMID:8710882

    Open questions at the time
    • Structural basis for VEID specificity unknown
    • In vivo genetic confirmation of lamin A as exclusive caspase-6 substrate needed
  3. 1999 High

    Establishing CASP6 as a neuronal caspase that cleaves APP and drives amyloidogenic processing opened its connection to Alzheimer's disease pathogenesis.

    Evidence Inhibitor studies (z-VEID-fmk), in vitro APP cleavage by recombinant caspase-6, pulse-chase labeling in primary human neurons

    PMID:10438520

    Open questions at the time
    • In vivo relevance to AD amyloid burden not yet confirmed
    • Upstream activation mechanism in neurons unknown
  4. 2000 High

    Demonstrating that caspase-6 activates caspase-3 (but not vice versa) in cerebellar neurons placed CASP6 upstream of caspase-3 in neuronal apoptotic cascades, revising its classification as a purely downstream executioner.

    Evidence Selective cell-permeable inhibitors and reconstitution in cerebellar granule cell extracts

    PMID:11279545

    Open questions at the time
    • Whether this hierarchical relationship holds in non-neuronal contexts unclear
    • Initiator caspase upstream of caspase-6 not identified
  5. 2001 High

    Identification of SATB1 and AP-2α as caspase-6 substrates expanded the functional repertoire to chromatin organization and transcription factor regulation during apoptosis.

    Evidence In vitro cleavage, site-directed mutagenesis, chromatin dissociation and DNA-binding assays in Jurkat and other cell lines

    PMID:11438643 PMID:11463840

    Open questions at the time
    • Whether caspase-6 cleavage of these factors occurs in vivo during physiological apoptosis uncertain
  6. 2002 High

    Genetic ablation of both CASP6 alleles in DT40 cells provided definitive evidence that caspase-6 is essential for lamin A/C cleavage and complete apoptotic morphology, while p53 was shown to directly transactivate the CASP6 gene through intronic response elements.

    Evidence DT40 knockout with complementation; ChIP, reporter assay, and caspase-6 inhibitor in p53-responsive cells

    PMID:11953316 PMID:12089322

    Open questions at the time
    • Mammalian knockout confirmation of lamin cleavage essentiality needed
    • Other transcription factors regulating CASP6 not explored
  7. 2004 High

    Discovery that caspase-6 cleaves tau at D13 and that active caspase-6 colocalizes with neurofibrillary tangles in AD brain provided direct biochemical and pathological evidence linking caspase-6 to tauopathy, while ARK5 phosphorylation at Ser257 was identified as a negative regulatory mechanism.

    Evidence In vitro tau cleavage with MS site identification, neoepitope antibody immunohistochemistry of AD brain; ARK5 kinase assay with S257A mutagenesis

    PMID:15273717 PMID:15277226 PMID:15356202

    Open questions at the time
    • Causal role of tau D13 cleavage in tangle progression unproven
    • Structural mechanism of Ser257 phosphorylation-mediated inhibition unknown
  8. 2006 High

    Identification of caspase-1 as a direct upstream activator of caspase-6 in primary human neurons established the inflammasome–caspase-6 connection and explained how neuronal caspase-6 becomes activated during trophic deprivation.

    Evidence Recombinant caspase-1 cleaves pro-caspase-6 in vitro; caspase-1 inhibitor and dominant-negative block caspase-6 activation in primary neurons

    PMID:16123779

    Open questions at the time
    • Inflammasome component responsible for caspase-1 activation in neurons not identified
    • Whether caspase-1-dependent activation occurs in non-neuronal cells unknown
  9. 2008 High

    Proteomic discovery of 24 neuronal caspase-6 substrates (including α-tubulin, spinophilin, drebrin) and demonstration that caspase-6 undergoes self-processing at D179/D193 expanded both its substrate network and the understanding of its activation mechanisms.

    Evidence 2D gel/LC-MS/MS proteomics in neurons, neoepitope validation in AD brain; site-directed mutagenesis of self-cleavage sites

    PMID:18487604 PMID:19133298

    Open questions at the time
    • Biological consequence of most newly identified substrate cleavages not assessed
    • Physiological context in which self-activation dominates unclear
  10. 2009 High

    Crystal structure of caspase-6 revealed constitutive dimerization with a unique latent conformation featuring a misaligned catalytic site and an elongated central α-helix replacing the substrate-binding β-sheet, explaining how the enzyme remains inactive until proteolytic maturation.

    Evidence X-ray crystallography with pre-steady-state kinetics

    PMID:19694615

    Open questions at the time
    • No structure of substrate-bound active form
    • Mechanism of allosteric activation not fully resolved
  11. 2010 High

    Multiple studies established CASP6 as a key mediator of neuronal axonal degeneration downstream of caspase-9 in ischemia, identified RIPK1 and IRAK-M as immunologically important substrates, and confirmed AMPK-dependent Ser257 phosphorylation as a regulatory mechanism, collectively broadening caspase-6's roles beyond classical apoptosis.

    Evidence Caspase-9 inhibitor in rat stroke model; RIPK1 cleavage with caspase-6 KO; IRAK-M cleavage-resistant mutant in Casp6−/− mice with sepsis; ARK5/AMPK kinase assays

    PMID:15273717 PMID:21098228 PMID:21677173 PMID:22858542

    Open questions at the time
    • How caspase-6 selects between pro-apoptotic and immunomodulatory substrate cleavage in vivo unclear
    • Structural basis for RIPK1 and IRAK-M recognition not determined
  12. 2012 High

    Crystal structures of Ser257 phosphomimetic mutants revealed the structural mechanism of AMPK-mediated inhibition — phospho-Ser257 clashes with Pro201 in the L2' loop, misaligning the substrate-binding groove — while Casp6−/− mice showed neuroprotection yet age-dependent brain volume increases and behavioral deficits, demonstrating a physiological homeostatic role.

    Evidence X-ray crystallography of S257D/S257E mutants with P201A rescue; Casp6−/− mice with MRI, behavioral testing, and neuronal culture neuroprotection

    PMID:22262731 PMID:22433863 PMID:22483120

    Open questions at the time
    • Whether Ser257 phosphorylation is dynamically regulated in neurons in vivo unconfirmed
    • Mechanism of caspase-6-dependent brain volume regulation unknown
  13. 2015 High

    Elucidation of the NLRP1→caspase-1→caspase-6 pathway in human neurons, validated in Nlrp1−/− and Casp1−/− mice, defined the complete inflammasome-to-executioner cascade driving axonal degeneration and Aβ42 ratio increase.

    Evidence siRNA of NLRP1 and caspase-1, Nlrp1−/− and Casp1−/− mice, ASC speck formation assay

    PMID:25744023

    Open questions at the time
    • Triggers of NLRP1 activation in aging/AD neurons not defined
    • Whether NLRP1–caspase-6 axis is druggable not tested
  14. 2018 High

    Identification of a tri-arginine exosite (R42–R44) required for protein (but not peptide) substrate hydrolysis, with HDX-MS revealing a substrate-binding platform spanning the NTD and 240's loop, established that caspase-6 uses an exosite mechanism for macromolecular substrate recognition.

    Evidence Site-directed mutagenesis of exosite residues, HDX-MS, protein vs. peptide kinetics

    PMID:30420425

    Open questions at the time
    • No co-crystal structure with protein substrate
    • How exosite contributes to substrate selectivity among different protein substrates not mapped
  15. 2020 High

    Discovery that caspase-6 performs a non-enzymatic scaffold function by facilitating RIPK3–ZBP1 PANoptosome assembly via RHIM-dependent binding during influenza infection, independent of catalytic activity, fundamentally expanded the gene's functional repertoire beyond proteolysis, while AMPK-mediated inhibition of caspase-6 was placed in a hepatoprotective FGF4→FGFR4→CaMKKβ→AMPK axis in NASH.

    Evidence Casp6−/− mice with IAV, co-IP of RIPK3–ZBP1–caspase-6, catalytic mutant dissection; AMPK KO mice, Bid cleavage assay, NASH models

    PMID:32029622 PMID:32298652

    Open questions at the time
    • RHIM-binding interface of caspase-6 not structurally characterized
    • Whether scaffold function extends to other PANoptosome-inducing stimuli unknown
    • In vivo relevance of the AMPK–caspase-6–Bid feedforward loop in human NASH not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structure of active caspase-6 bound to a protein substrate, how caspase-6 switches between enzymatic and scaffold functions in different cellular contexts, and the therapeutic potential of caspase-6 modulation in neurodegeneration and liver disease.
  • No co-crystal structure with protein substrate exists
  • Context-dependent regulatory switches between scaffold and enzymatic roles undefined
  • No clinical data on caspase-6-targeted interventions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 15 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-5357801 Programmed Cell Death 9 R-HSA-1643685 Disease 7 R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 3
Partners
CASP1CASP3CASP9NUAK1RIPK3TP53TXNZBP1
Complex memberships
PANoptosome (RIPK3–ZBP1–CASP6)

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CASP6 (Mch2 alpha) encodes a cysteine protease with activity against the fluorogenic peptide DEVD-AMC and cleaves poly(ADP-ribose) polymerase (PARP) in vitro; overexpression of Mch2 alpha (but not the Mch2 beta isoform) induces apoptosis in Sf9 insect cells. Recombinant protein expression, fluorogenic peptide cleavage assay, in vitro PARP cleavage, baculovirus overexpression Cancer research High 7796396
1996 CASP6 (Mch2 alpha) cleaves nuclear lamin A at the conserved VEID↓NG sequence in the coiled-coil rod domain, producing the apoptotic lamin A fragment; CPP32 (caspase-3) does not cleave lamin A, establishing distinct substrate specificities between these caspases. In vitro cleavage assay with recombinant IRPs, cell-free apoptosis extracts, Zn2+ inhibition, affinity labeling Proceedings of the National Academy of Sciences of the United States of America High 8710882
1996 CASP6 (Mch2) is processed from its zymogen to a proteolytically active dimeric species during apoptosis and by granzyme B; it functions downstream of death inhibitors Bcl-2, Bcl-xL, and CrmA; it cleaves lamin A to its signature apoptotic fragment, whereas caspase-3 (Yama) and caspase-7 (LAP3) do not, identifying CASP6 as an apoptotic laminase. In vitro cleavage assay, granzyme B processing, epistasis with Bcl-2/Bcl-xL/CrmA overexpression The Journal of biological chemistry High 8663580
1997 CASP6 (Mch2/caspase-6) and caspase-3 (CPP32) are the major active caspases present in apoptotic tumor cells in response to diverse apoptosis-inducing stimuli; both are present as multiple active species whose composition varies between cell lines. Active caspase detection approach using biotinylated caspase probes, multiple cell lines, multiple stimuli The EMBO journal High 9171342
1999 CASP6 is activated during serum deprivation-induced apoptosis in primary human neurons; it directly cleaves amyloid precursor protein (APP) at the C-terminus generating Capp3 and Capp6.5 fragments; caspase-6 inhibition prevents the serum deprivation-mediated increase in amyloid beta peptide, establishing a caspase-6-dependent amyloidogenic pathway. Inhibitor studies (z-VEID-fmk), in vitro cleavage of APP by recombinant caspase-6, pulse-chase metabolic labeling, immunoblot of human AD brain The Journal of biological chemistry High 10438520
2000 In cerebellar granule cell apoptosis induced by trophic support withdrawal, active caspase-6 can process and activate procaspase-3 in cellular extracts, whereas caspase-3 does not activate caspase-6; cell-permeable caspase-6 inhibitor prevents caspase-3 activation, placing caspase-6 upstream of caspase-3 in this pathway. Fluorogenic peptide assays, immunoblot, cell-permeable selective inhibitors (CP-VEID-cho, CP-DEVD-cho), ex vivo cerebellar granule cell system Cell death and differentiation High 11279545
2001 CASP6 cleaves SATB1 at amino acid position 254, separating the DNA-binding domains from the PDZ-like dimerization domain (aa 90–204); cleavage abolishes BUR-binding activity and causes rapid dissociation of SATB1 from chromatin in vivo, coinciding with high-molecular-weight chromatin fragmentation in apoptotic T cells. In vitro cleavage with caspase-6, site-directed mutagenesis, in vivo chromatin dissociation assay, Fas-induced apoptosis in Jurkat cells Molecular and cellular biology High 11463840
2002 Disruption of both CASP6 alleles in chicken DT40 cells reveals that caspase-6 activity is essential for lamin A/C cleavage during apoptosis and for complete chromatin condensation and apoptotic body formation when lamin A is present; lamins A and C are caspase-6-only substrates in this system. Gene disruption (both alleles), cell-free nuclear disassembly assay, complementation with exogenous caspase-6, caspase-6 inhibitor z-VEID-fmk The EMBO journal High 11953316
2002 p53 binds the third intron of the caspase-6 gene and transcriptionally activates it; p53-dependent increase in procaspase-6 protein enables increased caspase-6 activity and lamin A cleavage in response to Adriamycin; specific inhibition of caspase-6 blocks p53-mediated cell death. Chromatin immunoprecipitation (ChIP) of p53 to caspase-6 intron 3, reporter assay, immunoblot of lamin A cleavage, caspase-6 inhibitor Proceedings of the National Academy of Sciences of the United States of America High 12089322
2003 CBP (CREB-binding protein) is a caspase-6 substrate in primary neurons; caspase-6-mediated cleavage of CBP reduces CBP/p300 histone acetyltransferase activity during neuronal apoptosis, linking caspase-6 to transcriptional dysregulation and histone deacetylation in neurodegeneration. In vitro cleavage assay with recombinant caspase-6, HAT activity assay, primary neuron apoptosis model The EMBO journal High 14657026
2004 Active caspase-6 p20 subunit is present in neurofibrillary tangles, neuropil threads, and neuritic plaques in Alzheimer's disease brain; a neoepitope antibody to caspase-6-cleaved Tau detects intracellular and extracellular tangles and pretangles, indicating early caspase-6 activity in AD pathogenesis. Neoepitope antibodies to active caspase-6 p20 and caspase-6-cleaved Tau, immunohistochemistry of AD brain tissue The American journal of pathology High 15277226
2004 Caspase-6 cleaves the N-terminus of tau in vitro at D13 (a semicanonical cleavage site), preventing immunoreactivity with N-terminal tau antibodies; mass spectrometry confirmed this cleavage site, linking caspase-6-mediated N-terminal tau truncation to neurofibrillary tangle evolution in AD. In vitro cleavage of tau by recombinant caspase-6, mass spectrometry confirmation of cleavage site, immunohistochemistry The Journal of neuroscience : the official journal of the Society for Neuroscience High 15356202
2004 ARK5 kinase phosphorylates caspase-6 at Ser257, preventing its activation; mutant caspase-6 with S257A substitution is not inhibited by ARK5 phosphorylation and induces cell death even in ARK5-expressing cells; active ARK5 phosphorylates wild-type but not S257A caspase-6 in vitro. In vitro kinase assay with ARK5 and caspase-6, site-directed mutagenesis (S257A), cell death assay, ARK5 antisense Oncogene High 15273717
2004 Caspase-6 VEID-cleaving activity temporally correlates with procaspase-6 processing during lens fiber cell organelle elimination, distinct from caspase-3 activity seen in apoptosis, suggesting caspase-6 has a role in normal lens differentiation separate from classical apoptosis. Fluorogenic peptide (VEID-AFC) cleavage assay in lens extracts, Western blot for procaspase-6, transgenic mouse comparison The Journal of biological chemistry Medium 15161922
2006 Caspase-1 is an upstream activator of caspase-6 in primary human neurons: recombinant caspase-1 cleaves pro-caspase-6 in vitro to generate caspase-6 activity; caspase-1 inhibitor (Z-YVAD-fmk) prevents caspase-6 activation and cell death during serum deprivation. In vitro cleavage of pro-caspase-6 by recombinant caspase-1, caspase-1 inhibitor, dominant-negative caspase-1 construct, primary human neuron cultures Cell death and differentiation High 16123779
2006 Caspase-6 is selectively activated during resveratrol-induced apoptosis in colon cancer cells and its activity is essential for lamin A cleavage; partial knockdown of caspase-6 by siRNA significantly inhibits both lamin A cleavage and apoptosis; caspase-6 activation and lamin A cleavage are reduced in Bax-/- and p53-/- cells. siRNA knockdown, caspase-6 peptide inhibitors, Western blot for lamin A cleavage, TUNEL, flow cytometry Proteomics High 16518869
2007 p53 transcriptionally activates caspase-6 (and caspase-7) via direct DNA binding to intronic p53 response elements; ChIP, reporter gene, and EMSA assays confirm p53 binding; p53-/- cells fail to upregulate caspase-6/7 or activate them after cisplatin treatment. ChIP, reporter gene assay, EMSA, real-time PCR, p53-/- cells, p53 overexpression/inhibition Cell death and differentiation High 18064040
2008 Proteomic analysis identified 24 caspase-6 substrates in human neurons, including alpha-tubulin, alpha-actinin-4, spinophilin, and drebrin; caspase-6 cleavage sites were identified for drebrin, spinophilin, and alpha-tubulin; a neoepitope antibody to caspase-6-cleaved alpha-tubulin co-localizes with active caspase-6 in Alzheimer's disease lesions. 2D gel proteomics, LC/MS/MS, in vitro cleavage confirmation, neoepitope antibody, immunohistochemistry of AD brain Molecular & cellular proteomics : MCP High 18487604
2008 Self-activation of caspase-6: caspase-6 undergoes self-processing in vitro and in vivo; the pro-domain prevents self-activation in vivo but not in vitro; cleavage at either D179 or D193 in the linker is sufficient for activity; caspase-6 activity does not necessarily induce cell death in HEK293T cells. Site-directed mutagenesis of pro-domain (D23), linker cleavage sites (D179, D193), in vitro and in vivo activity assays Biochimica et biophysica acta High 19133298
2008 Active caspase-6 and caspase-6-cleaved huntingtin fragments (at aa 586) co-localize specifically in the nucleus of striatal cells; cell stress (staurosporine) causes nuclear translocation and activation of caspase-6 and increases nuclear 586 aa huntingtin fragments; caspase-2/3-generated 552 aa fragments localize to the perinuclear region. Neo-epitope antibodies to caspase fragments, subcellular fractionation, immunofluorescence, staurosporine treatment Human molecular genetics High 18445618
2008 Caspase-6 plays an important regulatory role in bile acid-induced hepatocyte apoptosis: caspase-6 is activated between caspase-9 and caspase-8 (GCDCA-induced activation of caspases-3/-7 is reduced in caspase-6-deficient cells); GCDCA-induced apoptosis is reduced by 50% in caspase-6-deficient HepG2-Ntcp cells and in primary rat hepatocytes pretreated with caspase-6 inhibitor. Caspase-6-deficient cells (siRNA/KO), caspase inhibitors (caspase-9, -6, -8), Western blot for caspase activation, primary rat hepatocytes The Journal of biological chemistry High 19017654
2009 Crystal structure of caspase-6 reveals it is a constitutive dimer independent of maturation state; the ligand-free structure shows a partially mature but latent conformation with misaligned catalytic machinery and absent substrate-recognition elements; an elongated central alpha-helix replaces the beta-sheet normally abutting substrate in other caspases. X-ray crystallography, pre-steady-state kinetics The Biochemical journal High 19694615
2009 Caspase-6 cleaves DJ-1 (a Parkinson's disease gene product); the PD-associated D149A mutation renders DJ-1 resistant to caspase-6 proteolysis, abolishing its protective phenotype; the caspase-6-derived C-terminal fragment of DJ-1 accounts for p53-dependent cell death. In vitro cleavage assay, site-directed mutagenesis (D149A), cell death assay, p53-dependent cell death measurement Cell death and differentiation High 19680261
2010 Valosin-containing protein (p97/VCP) is a caspase-6 substrate; caspase-6 cleaves p97 at VAPD(179) generating 28 and 20 kDa N-terminal fragments (not generated by caspase-3 or -7); the p97(1–179) fragment impairs ubiquitin-fusion degradation and N-end rule pathways and destabilizes endogenous p97; cleavage is detected in MCI and AD hippocampal neurons using a neoepitope antibody. In vitro cleavage assay, mass spectrometry cleavage site identification, overexpression of cleavage fragment, ubiquitin pathway functional assay, neoepitope immunohistochemistry The Journal of neuroscience : the official journal of the Society for Neuroscience High 20427671
2010 AMPK family member ARK5 phosphorylates caspase-6 at Ser257 to suppress its activation; active ARK5 phosphorylates wild-type but not S257A caspase-6 in vitro; this phosphorylation prevents procaspase-6 activation and thereby mediates resistance to FasL/Fas-induced cell death in colorectal cancer cells. In vitro kinase assay, S257A mutagenesis, cell death assays, ARK5 antisense Oncogene High 15273717
2010 Mutant nucleophosmin (NPMc+) directly binds the cleaved, active forms of caspase-6 and caspase-8 (but not procaspases), inhibiting their activities; this cytoplasmic NPMc+ interaction suppresses apoptosis and caspase-6/-8-mediated myeloid differentiation. Co-immunoprecipitation, direct binding assay, caspase activity assay, myeloid differentiation assay Blood High 20606168
2010 Caspase-9 activation in ischemic brain induces downstream caspase-6 activation, which mediates axonal loss before neuronal death; intranasal delivery of a caspase-9 inhibitor at 4 h post-reperfusion reduces caspase-6 activation and axonal loss, establishing caspase-9 as upstream of caspase-6 in ischemic neuronal death. Caspase-trapping technique in vivo, selective caspase-9 inhibitor (intranasal delivery), temporal/spatial expression analysis, rat stroke model The Journal of neuroscience : the official journal of the Society for Neuroscience High 21677173
2010 RIPK1 is an intrinsic pathway caspase-6 substrate; during intrinsic apoptosis, caspase-6 cleaves RIPK1 to prevent RIPK1-dependent pro-inflammatory cytokine production and inhibit the necroptotic pathway. In vitro cleavage assay, caspase-6 KO/inhibitor studies, cytokine measurement, necroptosis assay Cell death and differentiation High 22858542
2012 Phosphorylation of caspase-6 at Ser257 (by ARK5) inhibits its activity by causing a steric clash with Pro201 in the L2' loop, resulting in misalignment of the substrate-binding groove and preventing substrate binding; crystal structure of phosphomimetic S257D mutant reveals the structural basis; removal of the proline side chain (P201A) alleviates the clash and restores near-wild-type activity. X-ray crystallography of S257D phosphomimetic, site-directed mutagenesis (P201A), biochemical activity assay Structure (London, England : 1993) High 22483120
2012 Crystal structures of ΔproCASP6-S257E (phosphomimetic zymogen) and p20/p10-S257E (active form phosphomimetic) reveal that phosphorylation at Ser257 locks the zymogen in a TEVD(193)-bound inhibited state and causes steric hindrance in the active enzyme, preventing self-activation and substrate binding. X-ray crystallography of phosphomimetic mutants, molecular dynamics simulations, biochemical assays The Journal of biological chemistry High 22433863
2012 Caspase-6 deficiency protects neurons against excitotoxicity, nerve growth factor deprivation, and myelin-induced axonal degeneration; Casp6-/- mice show age-dependent increases in cortical and striatal volume, hypoactive phenotype, and learning deficits, revealing a physiological role of caspase-6 in neuronal homeostasis. Constitutive Casp6-/- mice, neuronal culture experiments, volumetric MRI, behavioral testing Human molecular genetics High 22262731
2012 Caspase-6 regulates B cell activation and differentiation into plasma cells by modifying cell cycle entry: Casp6 KO B cells enter G1 faster but do not increase S phase entry; instead they preferentially differentiate into syndecan-1+ plasma cells with enhanced antibody production. Casp6 knockout mice, cell cycle analysis (G0/G1/S), flow cytometry for plasma cell markers, serum Ig measurement Journal of immunology (Baltimore, Md. : 1950) High 18981099
2013 p53 increases caspase-6 mRNA levels and activity in tissues expressing mutant huntingtin; this is blocked by the p53 transcriptional inhibitor pifithrin-alpha but not by inhibition of p53's mitochondrial function, placing p53-dependent transcription upstream of caspase-6 activation in HD. Mouse embryonic fibroblasts from YAC128 mice, pifithrin-alpha treatment, qRT-PCR, caspase-6 activity assay, lamin A cleavage Human molecular genetics High 24070868
2015 The NLRP1 inflammasome activates caspase-1, which in turn activates caspase-6 in human neurons; NLRP1 or caspase-1 siRNA abolishes stress-induced caspase-6 activation; this NLRP1/Casp1/Casp6 pathway is confirmed in vivo in Nlrp1-/- and Casp1-/- mice and promotes axonal degeneration and amyloid beta 42 ratio increase. siRNA knockdown of NLRP1 and caspase-1, cell-free caspase-1 activation assay, Nlrp1-/- and Casp1-/- mice, ASC speck formation assay Cell death and differentiation High 25744023
2018 A tri-arginine exosite patch (Arg42–Arg44) at the hinge between the N-terminal domain and core of caspase-6 is required for protein substrate hydrolysis but not short peptide cleavage; mutagenesis of this exosite and the cancer-associated R44K mutation markedly reduce protein substrate turnover; hydrogen-deuterium exchange MS reveals a substrate-binding platform encompassing the NTD and 240's region. Site-directed mutagenesis of exosite residues, hydrogen-deuterium exchange MS, protein and peptide substrate kinetics The Journal of biological chemistry High 30420425
2019 Thioredoxin-1 (Trx1) acts as a gatekeeper for caspase-6 activation: reduced Trx1 decreases caspase-6 enzymatic activity and lamin-B1 cleavage, while fully oxidized Trx1 enhances caspase-6 activation; inhibition of Trx1 promotes nuclear lamin-B1 cleavage in a caspase-6-dependent manner, upstream of caspase-3/7. Pharmacological/genetic Trx1 inhibition, cell-free nuclear preparations, purified enzymatic assays with reduced/oxidized Trx1, caspase-6 inhibitor, lamin-B1 cleavage assay Free radical biology & medicine High 30769159
2020 Caspase-6 facilitates RIPK3–ZBP1 interaction during influenza A virus (IAV) infection: caspase-6 interacts with RIPK3 through RHIM-dependent binding and promotes ZBP1–RIPK3 association and PANoptosome assembly; this function is independent of caspase-6 enzymatic activity. Caspase-6 is also required for alternative activation of alveolar macrophages during IAV infection. Casp6-/- mice, co-immunoprecipitation of RIPK3–ZBP1–caspase-6, catalytic mutant of caspase-6, IAV infection model, macrophage polarization assay Cell High 32298652
2020 AMPK phosphorylates caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check; when AMPK activity is suppressed (as in NASH), caspase-6 is activated by caspase-3 or -7; active caspase-6 cleaves Bid to induce cytochrome c release, generating a feedforward apoptotic loop; liver-specific AMPK knockout aggravates NASH damage. AMPK phosphorylation of caspase-6 (kinase assay), AMPK KO mice (liver-specific), caspase-6 inhibition in vivo, Bid cleavage assay, human and mouse NASH models Science (New York, N.Y.) High 32029622
2010 Neutrophil-macrophage contact induces caspase-6 activity in alveolar macrophages; caspase-6 cleaves IRAK-M, relieving its inhibition of TLR signaling; without caspase-6 expression, PMN stimulation fails to cleave IRAK-M, degrade IκBα, or induce TNF-α; Casp6-/- mice subjected to sepsis show impaired TNF-α production and decreased mortality. Caspase-6 KO mice (cecal ligation and puncture), IRAK-M cleavage-resistant mutant, PMN-macrophage co-culture, TNF-α measurement, IκBα degradation Journal of immunology (Baltimore, Md. : 1950) High 21098228
2001 Transcription factor AP-2alpha is preferentially cleaved by caspase-6 in vitro at Asp19 (DRHD sequence); this cleavage leads to AP-2alpha degradation by the proteasome and loss of DNA-binding activity; mutation of D19A abolishes cleavage by all three caspases tested; cells expressing mutant AP-2alpha are resistant to TNF-alpha-induced apoptosis. In vitro cleavage with recombinant caspase-6/1/3, D19A mutagenesis, proteasome inhibitor, DNA-binding EMSA, apoptosis assay Molecular and cellular biology High 11438643
2002 Human UFD2 (ubiquitin fusion degradation protein) is efficiently cleaved by caspase-6 and granzyme B at Asp123; caspases-3 and -7 cleave at an upstream site (Asp109) with ~10-fold lower efficiency; truncation at the granzyme B/caspase-6 cleavage site abolishes E3-like ubiquitination activity of UFD2. In vitro cleavage kinetics with recombinant caspases, granzyme B, mass spectrometry for cleavage sites, ubiquitination activity assay The Biochemical journal High 11802788
2022 FGF4 activates an FGFR4→CaMKKβ→AMPK→Caspase-6 signaling axis in the liver; AMPK phosphorylation of caspase-6 downstream of FGFR4 activation inhibits hepatocellular apoptosis and reduces liver damage in NAFLD/NASH models. Recombinant FGF4 administration, FGFR4-selective inhibitor, AMPK activation/inhibition, caspase-6 activity assay, mouse NAFLD/NASH models Hepatology (Baltimore, Md.) High 35152446

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proceedings of the National Academy of Sciences of the United States of America 464 8710882
2020 Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense. Cell 419 32298652
1995 Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family. Cancer research 405 7796396
1996 The CED-3/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A. The Journal of biological chemistry 385 8663580
1997 Multiple species of CPP32 and Mch2 are the major active caspases present in apoptotic cells. The EMBO journal 327 9171342
2020 An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science (New York, N.Y.) 259 32029622
2015 Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell death and differentiation 252 25744023
2003 Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration. The EMBO journal 252 14657026
2004 Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. The American journal of pathology 246 15277226
1999 Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease. The Journal of biological chemistry 244 10438520
2002 Caspase-6 gene disruption reveals a requirement for lamin A cleavage in apoptotic chromatin condensation. The EMBO journal 218 11953316
2001 Molecular cloning and functional characterization of MCH2, a novel human MCH receptor. The Journal of biological chemistry 191 11274220
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