{"gene":"SEPTIN4","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2004,"finding":"ARTS (Sept4_i2) is released from mitochondria upon pro-apoptotic stimuli and directly binds XIAP in vitro; binding is specific and required for pro-apoptotic function, as ARTS mutants that fail to bind XIAP also fail to induce apoptosis. ARTS binding to XIAP leads to decreased XIAP protein levels and caspase activation.","method":"In vitro binding assay with recombinant proteins, coimmunoprecipitation, cell-based apoptosis assays, mutagenesis of ARTS and related septins","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted direct binding in vitro with recombinant proteins, complemented by cell-based functional assays and mutagenesis showing binding is required for apoptotic activity","pmids":["15029247"],"is_preprint":false},{"year":2010,"finding":"ARTS binds XIAP at the BIR1 domain (distinct from caspase-binding sites) and interacts with the E3 ligase Siah-1, acting as an adaptor to bridge Siah-1 to XIAP, thereby inducing XIAP ubiquitination and degradation. Cells lacking either Siah or ARTS have elevated steady-state XIAP levels.","method":"Co-immunoprecipitation, ubiquitination assays, genetic knockdown/knockout of ARTS and Siah in cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying BIR1 as binding domain, E3 ligase interaction, and complementary loss-of-function data in cells; single lab but multiple orthogonal methods","pmids":["21185211"],"is_preprint":false},{"year":2017,"finding":"ARTS forms a ternary complex with XIAP and Bcl-2 at the outer mitochondrial membrane upon apoptotic induction. ARTS binding to Bcl-2 involves the BH3 domain of Bcl-2; XIAP serves as an E3 ligase ubiquitinating Bcl-2 at Lysine 17, and ARTS is essential for this process. A Bcl-2 K17A mutant has increased stability and stronger anti-apoptotic potency. Bcl-2 ubiquitylation is reduced in both XIAP- and Sept4/ARTS-deficient MEFs.","method":"Co-immunoprecipitation (ternary complex), ubiquitylation assays, site-directed mutagenesis (K17A Bcl-2, BH3 domain), MEF knockout cells, mass spectrometry","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, reciprocal Co-IP, ubiquitylation assays in knockout MEFs establishing mechanistic details","pmids":["29020630"],"is_preprint":false},{"year":2005,"finding":"ARTS protein levels are kept low in healthy cells through constant ubiquitin-mediated proteasomal degradation. Upon pro-apoptotic stimuli, ARTS ubiquitination is inhibited, leading to increased ARTS levels, decreased Bcl-2 and Bcl-xL protein levels, cytochrome c release, and apoptosis.","method":"Ubiquitination assays, proteasome inhibitor treatments, overexpression and protein stability experiments in cell lines","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based ubiquitination assays with functional readouts, single lab with multiple methods","pmids":["15837787"],"is_preprint":false},{"year":2012,"finding":"Parkin (E3-ubiquitin ligase) binds both ARTS (Sept4_i2) and Sept4_i1 but specifically ubiquitinates and degrades only ARTS via the ubiquitin-proteasome system. Parkin loss-of-function increases ARTS levels and promotes apoptosis; Parkin overexpression protects cells from ARTS-induced apoptosis. High ARTS levels are found in rat brains treated with 6-OHDA.","method":"Co-immunoprecipitation, ubiquitination assays, Parkin overexpression and knockdown, neuronal cell culture apoptosis assays, in vivo 6-OHDA rat model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, gain- and loss-of-function, single lab with multiple orthogonal methods","pmids":["22792159"],"is_preprint":false},{"year":2010,"finding":"Deletion of the mouse Sept4 gene (encoding ARTS) results in increased numbers of hematopoietic stem and progenitor cells, elevated XIAP protein, increased resistance to cell death, and accelerated tumor development in an Eμ-Myc background. These phenotypes are partially suppressed by inactivation of XIAP, placing ARTS upstream of XIAP in the apoptotic pathway.","method":"Sept4 knockout mice, Eμ-Myc tumor model, XIAP genetic inactivation (epistasis), FACS of hematopoietic stem/progenitor cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double knockout, in vivo tumor model, stem cell quantification; multiple orthogonal in vivo approaches","pmids":["20952537"],"is_preprint":false},{"year":2013,"finding":"Sept4/ARTS-deficient mice have elevated numbers of hair follicle stem cells (HFSCs) protected against apoptosis, display improved wound healing and hair follicle regeneration. Inactivation of XIAP, a direct ARTS target, abrogates these phenotypes, demonstrating ARTS acts via XIAP to regulate stem cell apoptosis and tissue regeneration.","method":"Sept4/ARTS knockout mice, lineage tracing, XIAP genetic inactivation, wound healing assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (ARTS KO + XIAP KO double mutant rescues phenotype), lineage tracing, multiple orthogonal methods","pmids":["23788729"],"is_preprint":false},{"year":2018,"finding":"ARTS is highly expressed in intestinal stem cell niche cells; its deletion protects Lgr5+ and Paneth cells from apoptosis, leading to augmented crypt proliferation, enhanced Wnt/β-catenin signaling, and massive cystic organoids. ARTS interacts with XIAP in intestinal crypt cells and deletion of XIAP abrogates Sept4/ARTS-/- phenotypes.","method":"Sept4/ARTS knockout mice, intestinal organoid culture, co-immunoprecipitation (ARTS-XIAP), XIAP genetic epistasis, Wnt/β-catenin signaling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO phenotype, organoid functional assay, XIAP epistasis, Co-IP; multiple orthogonal methods in single study","pmids":["30389919"],"is_preprint":false},{"year":2021,"finding":"ARTS is a p53 target gene: p53 transcriptionally activates the ARTS promoter via a p53-responsive DNA element. In turn, ARTS binds p53 protein and sequesters it at mitochondria, enhancing interaction between p53 and Bcl-XL, thereby promoting mitochondrial apoptosis. Ectopic ARTS augments DNA damage-induced apoptosis; ablation of ARTS impairs p53-induced apoptosis.","method":"Luciferase reporter assay (ARTS promoter), ChIP (p53 binding to ARTS promoter), co-immunoprecipitation (ARTS-p53, p53-Bcl-XL), ARTS knockdown/overexpression, γ-irradiation in mice","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, reciprocal Co-IP, reporter assay, in vivo irradiation, gain- and loss-of-function; multiple orthogonal methods in single study","pmids":["33627621"],"is_preprint":false},{"year":2011,"finding":"The Sept4 gene encodes two major isoforms (Sept4_i1/H5/PNUTL2 and Sept4_i2/ARTS) through a combination of two distinct promoters, differential splicing, and intron retention. ARTS is localized at mitochondria and promotes apoptosis, while Sept4_i1 is non-apoptotic; these structural differences explain their divergent biological activities.","method":"Molecular characterization (promoter analysis, splicing analysis), subcellular fractionation/immunolocalization","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of gene structure and isoform-specific localization, review synthesizing prior experimental data; single lab","pmids":["21824006"],"is_preprint":false},{"year":2020,"finding":"WWP2 (a HECT-type E3 ubiquitin ligase) interacts with the GTPase domain of Septin4 and ubiquitinates Septin4 at K174, promoting its degradation via the ubiquitin-proteasome system. This inhibits the Septin4-PARP1 endothelial damage complex. Endothelial/myeloid-specific WWP2 knockout in mice aggravates oxidative stress-induced endothelial injury.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K174), WWP2 knockout mice (endothelial-specific), in vitro endothelial injury assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assays with mutagenesis, in vivo conditional KO; multiple orthogonal methods","pmids":["31924572"],"is_preprint":false},{"year":2018,"finding":"Septin4 directly interacts with PARP1 (identified as a novel binding partner), and this interaction is enhanced under oxidative stress. Knockdown and overexpression of Septin4 modulate ROS production and apoptosis in endothelial cells under oxidative stress.","method":"Co-immunoprecipitation (Septin4-PARP1), Septin4 knockdown and overexpression, ROS assays, apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP identifying novel binding partner, gain- and loss-of-function with functional readouts; single lab, single Co-IP method","pmids":["29366480"],"is_preprint":false},{"year":2023,"finding":"SIRT2 deacetylates Septin4 at lysine 174 (K174); hyperacetylation of K174 (mimicked by K174Q mutant) activates the cleaved-PARP1-cleaved-caspase3 pathway and exacerbates angiotensin II-induced hypertensive renal injury. Septin4-K174R (deacetylation mimic) rescues podocyte apoptosis. SIRT2 interacts with the Septin4 GTPase domain.","method":"Transgenic SIRT2 mice, SIRT2 knockout mice, septin4-K174Q and K174R mutant knock-in mice, co-immunoprecipitation, mass spectrometry, proteomic/acetyl-proteomics, Western blot","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-directed mutagenesis (K174Q/R), multiple transgenic/KO mouse models, Co-IP, mass spectrometry; mechanistic mutagenesis with in vivo validation","pmids":["36786216"],"is_preprint":false},{"year":2020,"finding":"Septin4 modulates autophagy in vascular smooth muscle cells (VSMCs); overexpression of Septin4 reduces autophagy levels and decreases Ang-II-induced VSMC proliferation and migration. Blocking autophagy with chloroquine further restrains proliferation and migration in Septin4-overexpressing VSMCs, confirming Septin4 regulates these processes via autophagy.","method":"Septin4 overexpression in VSMCs, autophagy inhibition with chloroquine, proliferation and migration assays, in vivo Ang-II infusion in mice","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pharmacological epistasis (chloroquine), in vivo model; single lab, limited mechanistic depth on direct binding","pmids":["32085901"],"is_preprint":false},{"year":2020,"finding":"Septin4 forms a complex with SIRT1 and STAT3 (co-immunoprecipitation), enhancing the interaction between SIRT1 and STAT3 and promoting SIRT1-regulated STAT3-K685 deacetylation and STAT3-Y705 dephosphorylation, thereby inhibiting PDGF-BB-induced HAVSMC proliferation, migration, and phenotypic transformation.","method":"Co-immunoprecipitation (Septin4-SIRT1-STAT3 complex), Septin4 knockdown and overexpression, phosphorylation and acetylation site analysis, VSMC functional assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying ternary complex, gain- and loss-of-function with specific post-translational modification readouts; single lab","pmids":["32025217"],"is_preprint":false},{"year":2021,"finding":"Septin4 interacts with HIF-1α at the Septin4 GTPase domain and enhances the binding between HIF-1α and the E3 ubiquitin ligase VHL, promoting HIF-1α ubiquitin-mediated degradation. By reducing HIF-1α levels, Septin4 aggravates hypoxia-induced cardiomyocyte apoptosis.","method":"Co-immunoprecipitation (Septin4-HIF-1α, HIF-1α-VHL), GTPase domain mapping, ubiquitination assays, cardiomyocyte hypoxia model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying novel binding partners, domain mapping, ubiquitination assays with functional apoptosis readout; single lab","pmids":["34230460"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function mutations in SEPTIN4 (c.A721T/p.R241* and c.C205T/p.R69*) in humans cause thin midpiece spermatozoa, annulus loss, disorganized mitochondrial sheath, and asthenoteratozoospermia. SEPT4 is required for SEPT-based annulus formation and correct localization of SEPTIN subunits and the anion transporter SLC26A8 at the sperm annulus.","method":"Human genetics (biallelic variant identification), immunofluorescence, immunoblotting (TOMM20, HSP60, SLC26A8), electron microscopy of sperm ultrastructure","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — human loss-of-function variants with multiple orthogonal structural and localization assays confirming SEPT4's role in annulus formation and sperm midpiece integrity","pmids":["36135717"],"is_preprint":false},{"year":2020,"finding":"In Sept4/ARTS-/- mice, neutrophil apoptosis, macrophage efferocytosis, and macrophage reprogramming to pro-resolving phenotype are all impaired during resolution of inflammation (zymosan-induced peritonitis). ARTS overexpression in leukocytes in vitro promotes anti-inflammatory behavior, indicating ARTS acts upstream of XIAP to regulate apoptosis-dependent resolution of inflammation.","method":"Sept4/ARTS-/- mice, zymosan-induced peritonitis model, ARTS overexpression in leukocytes, cytokine measurements, efferocytosis assays","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with specific cellular phenotypes, in vitro gain-of-function; single lab, multiple readouts","pmids":["32564202"],"is_preprint":false},{"year":2014,"finding":"Septin4_i1 induces apoptosis in hepatic stellate cells (LX-2) by upregulating PPAR-γ and reducing phosphorylated Akt and Bcl-2 expression. Cleaved-caspase-3 increases upon Septin4_i1 overexpression, and this effect is reversed by a PPAR-β/δ agonist (GW501516, which enhances Akt signaling) or a PPAR-γ antagonist (GW9662).","method":"Overexpression of Septin4_i1 in LX-2 cells, pharmacological inhibitor/agonist treatment, Western blot for PPAR-γ, Akt, Bcl-2, caspase-3","journal":"The journal of histochemistry and cytochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pharmacological epistasis identifying PPAR-γ/Akt/Bcl-2 pathway; single lab, cell-line-based","pmids":["25527525"],"is_preprint":false},{"year":2020,"finding":"A small molecule (A4) mimicking ARTS binds XIAP at a distinct pocket in the BIR3 domain (not the caspase-binding site, consistent with ARTS binding at BIR1 region), stimulates poly-ubiquitylation and UPS-mediated degradation of XIAP and Bcl-2 (but not cIAP1), activates caspase-9 and -3, and induces apoptosis. XIAP overexpression rescues cells from A4-induced death.","method":"Microscale thermophoresis (binding assay), ubiquitylation assays, caspase activation assays, XIAP overexpression rescue, proteome analysis of cancer cell lines","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biophysical binding assay, ubiquitylation assays, functional rescue; validates ARTS binding pocket in XIAP; single lab","pmids":["32587235"],"is_preprint":false}],"current_model":"SEPTIN4/ARTS (Sept4_i2) is a mitochondria-localized pro-apoptotic protein that, upon apoptotic stimulation, translocates to the cytosol and directly binds XIAP at its BIR1 domain, acting as an adaptor for the E3 ligase Siah-1 to ubiquitinate and degrade XIAP; it simultaneously brings XIAP and Bcl-2 into a ternary complex enabling XIAP-mediated ubiquitination and proteasomal degradation of Bcl-2 at K17; ARTS also binds and sequesters p53 at mitochondria to enhance p53-Bcl-XL interaction and promote mitochondrial apoptosis, while in living cells ARTS itself is kept at low levels by ubiquitin-proteasomal degradation via Parkin and WWP2 (the latter targeting K174), and by SIRT2-mediated deacetylation of K174, which modulates ARTS activity in podocytes; beyond its apoptotic role, Septin4 is an essential structural component of the sperm annulus (required for midpiece integrity and SLC26A8 localization), and interacts with PARP1, SIRT1-STAT3, and HIF-1α-VHL complexes to regulate endothelial injury, vascular smooth muscle cell behavior, and cardiomyocyte apoptosis."},"narrative":{"mechanistic_narrative":"SEPTIN4 encodes two functionally divergent isoforms generated by alternative promoters, splicing, and intron retention: the mitochondrial pro-apoptotic isoform Sept4_i2/ARTS and the non-apoptotic Sept4_i1 [PMID:21824006]. ARTS is a tumor-suppressive antagonist of the inhibitor-of-apoptosis protein XIAP: upon pro-apoptotic stimulation it is released from mitochondria and binds XIAP directly at the BIR1 domain, a site distinct from the caspase-binding pockets [PMID:15029247, PMID:21185211]. Bound ARTS acts as an adaptor that bridges the E3 ligase Siah-1 to XIAP, driving XIAP ubiquitination and proteasomal degradation and thereby relieving caspase inhibition [PMID:21185211]. ARTS additionally nucleates a ternary complex with XIAP and Bcl-2 in which XIAP ubiquitinates Bcl-2 at Lys17 to promote its degradation, and it binds and sequesters p53 at mitochondria to enhance the p53–Bcl-XL interaction; ARTS is itself a transcriptional target of p53 [PMID:29020630, PMID:33627621]. This ARTS–XIAP axis governs apoptosis-dependent control of stem cell pools and tissue homeostasis: Sept4/ARTS loss elevates XIAP, protects hematopoietic, hair-follicle, and intestinal stem cells from death, accelerates tumorigenesis, and impairs inflammation resolution, with all phenotypes reverted by XIAP inactivation [PMID:20952537, PMID:23788729, PMID:30389919, PMID:32564202]. In healthy cells ARTS is held at low levels by constitutive ubiquitin–proteasome turnover, mediated by Parkin and by WWP2-catalyzed ubiquitination at Lys174, with SIRT2-dependent deacetylation of the same residue modulating its pro-apoptotic activity in podocytes [PMID:15837787, PMID:22792159, PMID:31924572, PMID:36786216]. Beyond apoptosis, Septin4 is an essential structural component of the sperm annulus required for midpiece integrity and SLC26A8 localization, and biallelic loss-of-function SEPTIN4 mutations cause asthenoteratozoospermia in humans [PMID:36135717]. In the vasculature and myocardium Septin4 binds PARP1, SIRT1–STAT3, and the HIF-1α–VHL machinery to regulate endothelial injury, smooth muscle cell behavior, and cardiomyocyte apoptosis [PMID:29366480, PMID:32025217, PMID:34230460].","teleology":[{"year":2004,"claim":"Established that the SEPTIN4 isoform ARTS is a mitochondrial pro-apoptotic protein that acts directly on XIAP, defining its core molecular target.","evidence":"In vitro binding with recombinant proteins, Co-IP, cell-based apoptosis assays, and mutagenesis in cell lines","pmids":["15029247"],"confidence":"High","gaps":["Did not identify the binding domain on XIAP","Mechanism of how binding lowers XIAP levels left undefined"]},{"year":2005,"claim":"Showed why ARTS is dormant in living cells — it is held at low levels by constitutive ubiquitin-proteasome degradation that is relieved upon apoptotic signaling.","evidence":"Ubiquitination assays, proteasome inhibition, and protein stability experiments in cell lines","pmids":["15837787"],"confidence":"Medium","gaps":["The responsible E3 ligase was not identified here","Signal that inhibits ARTS ubiquitination upon apoptotic induction unresolved"]},{"year":2010,"claim":"Resolved the molecular mechanism of XIAP destruction, showing ARTS binds the BIR1 domain and bridges the E3 ligase Siah-1 to drive XIAP ubiquitination.","evidence":"Reciprocal Co-IP, ubiquitination assays, and loss-of-function in ARTS- and Siah-deficient cells","pmids":["21185211"],"confidence":"High","gaps":["Stoichiometry of the ARTS–Siah-1–XIAP complex not defined","No structural model of the BIR1 interface"]},{"year":2010,"claim":"Placed ARTS genetically upstream of XIAP in vivo, demonstrating it is a tumor suppressor that restrains hematopoietic stem cell survival.","evidence":"Sept4 knockout mice, Eµ-Myc tumor model, XIAP epistasis double knockout, FACS of stem/progenitor cells","pmids":["20952537"],"confidence":"High","gaps":["Cell-type-specific contributions to tumor suppression not dissected","Does not address non-XIAP targets"]},{"year":2011,"claim":"Explained the divergent biology of the locus by characterizing two isoforms with distinct promoters, splicing, and subcellular localization.","evidence":"Promoter and splicing analysis plus subcellular fractionation/immunolocalization","pmids":["21824006"],"confidence":"Medium","gaps":["Functional role of Sept4_i1 left largely undefined","Synthesis of prior data rather than new mechanism"]},{"year":2012,"claim":"Identified Parkin as an E3 ligase that selectively degrades ARTS, linking ARTS turnover to a neuronal survival pathway.","evidence":"Reciprocal Co-IP, ubiquitination assays, Parkin gain/loss-of-function, neuronal apoptosis assays, and a 6-OHDA rat model","pmids":["22792159"],"confidence":"Medium","gaps":["Ubiquitination site on ARTS not mapped","Relationship between Parkin and other ARTS ligases unresolved"]},{"year":2013,"claim":"Extended the ARTS–XIAP axis to adult tissue regeneration, showing ARTS controls hair follicle stem cell apoptosis via XIAP.","evidence":"Sept4/ARTS knockout mice, lineage tracing, XIAP epistasis, wound healing assays","pmids":["23788729"],"confidence":"High","gaps":["Upstream signals triggering ARTS in stem cells unknown","Whether effect is cell-autonomous within the niche not fully resolved"]},{"year":2017,"claim":"Expanded ARTS function beyond XIAP degradation, showing it nucleates an XIAP–Bcl-2 ternary complex enabling Bcl-2 ubiquitination at K17.","evidence":"Co-IP of the ternary complex, ubiquitylation assays, K17A/BH3 mutagenesis, knockout MEFs, mass spectrometry","pmids":["29020630"],"confidence":"High","gaps":["Spatial/temporal coordination with XIAP degradation not resolved","Bcl-xL regulation mechanism less defined than Bcl-2"]},{"year":2018,"claim":"Demonstrated ARTS restrains intestinal stem cell survival and Wnt signaling, with phenotypes XIAP-dependent.","evidence":"Knockout mice, intestinal organoids, ARTS-XIAP Co-IP, XIAP epistasis, Wnt/β-catenin assays","pmids":["30389919"],"confidence":"High","gaps":["Mechanistic link between ARTS loss and Wnt activation indirect","Direct ARTS effectors in crypt cells beyond XIAP unknown"]},{"year":2018,"claim":"Identified PARP1 as a novel Septin4 partner relevant to oxidative endothelial stress.","evidence":"Co-IP, Septin4 knockdown/overexpression, ROS and apoptosis assays in endothelial cells","pmids":["29366480"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal/structural validation","Functional consequence of the Septin4-PARP1 complex on PARP1 activity unclear"]},{"year":2020,"claim":"Defined WWP2 as a HECT E3 ligase that ubiquitinates Septin4 at K174 to suppress the Septin4-PARP1 endothelial damage complex.","evidence":"Co-IP, ubiquitination assays, K174 mutagenesis, endothelial-specific WWP2 knockout mice","pmids":["31924572"],"confidence":"High","gaps":["Interplay between WWP2 and Parkin in Septin4 turnover not addressed","Isoform specificity of K174 ubiquitination not detailed"]},{"year":2020,"claim":"Showed Septin4 promotes formation of a SIRT1–STAT3 complex to suppress vascular smooth muscle cell proliferation through STAT3 deacetylation/dephosphorylation.","evidence":"Reciprocal Co-IP of ternary complex, gain/loss-of-function, STAT3 PTM analysis, VSMC functional assays","pmids":["32025217"],"confidence":"Medium","gaps":["Direct vs scaffolding role of Septin4 in the complex unclear","Single-lab finding without structural mapping"]},{"year":2020,"claim":"Linked Septin4 to autophagy regulation in vascular smooth muscle cells controlling proliferation and migration.","evidence":"Septin4 overexpression, chloroquine epistasis, proliferation/migration assays, in vivo Ang-II infusion","pmids":["32085901"],"confidence":"Medium","gaps":["No direct molecular link between Septin4 and the autophagy machinery","Mechanism of autophagy suppression undefined"]},{"year":2020,"claim":"Established a role for ARTS in resolution of inflammation through control of neutrophil apoptosis and macrophage efferocytosis.","evidence":"Sept4/ARTS knockout mice, zymosan peritonitis, leukocyte overexpression, efferocytosis and cytokine assays","pmids":["32564202"],"confidence":"Medium","gaps":["Whether macrophage reprogramming is XIAP-dependent not directly tested","Cell-intrinsic vs extrinsic contributions not separated"]},{"year":2020,"claim":"Validated the ARTS-binding pocket on XIAP pharmacologically, showing a small molecule recapitulates ARTS-driven XIAP/Bcl-2 degradation and apoptosis.","evidence":"Microscale thermophoresis, ubiquitylation and caspase assays, XIAP rescue, cancer cell proteome analysis","pmids":["32587235"],"confidence":"Medium","gaps":["Compound binds BIR3, leaving exact correspondence to ARTS BIR1 site partly inferential","Selectivity in vivo not established"]},{"year":2021,"claim":"Connected ARTS to the p53 axis as both a transcriptional target and a mitochondrial p53-sequestering factor that promotes apoptosis.","evidence":"Luciferase reporter, ChIP, reciprocal Co-IP, gain/loss-of-function, in vivo irradiation","pmids":["33627621"],"confidence":"High","gaps":["Stoichiometry and structural basis of ARTS-p53 binding unknown","Interplay with the XIAP-degradation function not integrated"]},{"year":2021,"claim":"Showed Septin4 enhances HIF-1α–VHL binding to drive HIF-1α degradation, aggravating cardiomyocyte apoptosis under hypoxia.","evidence":"Co-IP, GTPase domain mapping, ubiquitination assays, cardiomyocyte hypoxia model","pmids":["34230460"],"confidence":"Medium","gaps":["Direct contact residues between Septin4 and HIF-1α undefined","Single-lab finding without in vivo validation"]},{"year":2022,"claim":"Defined a structural, apoptosis-independent role for SEPTIN4, establishing it as essential for the sperm annulus and a cause of human asthenoteratozoospermia.","evidence":"Human biallelic loss-of-function variants, immunofluorescence, immunoblotting, electron microscopy of sperm","pmids":["36135717"],"confidence":"High","gaps":["Mechanism of SLC26A8 mislocalization not detailed","How structural and apoptotic functions are partitioned between isoforms unclear"]},{"year":2023,"claim":"Identified an acetylation switch on Septin4-K174 controlled by SIRT2 that tunes its pro-apoptotic activity in hypertensive renal injury.","evidence":"Transgenic/knockout SIRT2 mice, K174Q/R knock-in mice, Co-IP, mass spectrometry, acetyl-proteomics","pmids":["36786216"],"confidence":"High","gaps":["Crosstalk between K174 acetylation and K174 ubiquitination by WWP2 not directly resolved","Generalizability beyond podocytes untested"]},{"year":null,"claim":"How the apoptotic ARTS isoform and the structural/scaffolding Septin4 functions are coordinated at the protein level, and whether the cytoplasmic vascular/cardiac partner interactions (PARP1, SIRT1-STAT3, HIF-1α-VHL) involve canonical septin filament assembly, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ARTS-XIAP or ARTS-p53 complexes","Isoform-specific contributions to vascular and cardiac phenotypes not dissected","Relationship between septin polymerization and the apoptotic adaptor function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,8,14,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,8,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,5,6,7,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,4,10,12,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[16]}],"complexes":["ARTS-XIAP-Siah-1 complex","ARTS-XIAP-Bcl-2 ternary complex","Septin4-SIRT1-STAT3 complex","sperm annulus"],"partners":["XIAP","SIAH1","BCL2","TP53","PARK2","WWP2","SIRT2","PARP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43236","full_name":"Septin-4","aliases":["Bradeion beta","Brain protein H5","CE5B3 beta","Cell division control-related protein 2","hCDCREL-2","Peanut-like protein 2"],"length_aa":996,"mass_kda":112.4,"function":"Filament-forming cytoskeletal GTPase (Probable). Pro-apoptotic protein involved in LGR5-positive intestinal stem cell and Paneth cell expansion in the intestines, via its interaction with XIAP (By similarity). May also play a role in the regulation of cell fate in the intestine (By similarity). Positive regulator of apoptosis involved in hematopoietic stem cell homeostasis; via its interaction with XIAP (By similarity). Negative regulator of repair and hair follicle regeneration in response to injury, due to inhibition of hair follicle stem cell proliferation, potentially via its interaction with XIAP (By similarity). Plays an important role in male fertility and sperm motility (PubMed:36135717). During spermiogenesis, essential for the establishment of the annulus (a fibrous ring structure connecting the midpiece and the principal piece of the sperm flagellum) which is a requisite for the structural and mechanical integrity of the sperm (PubMed:36135717). Involved in the migration of cortical neurons and the formation of neuron leading processes during embryonic development (By similarity). Required for dopaminergic metabolism in presynaptic autoreceptors; potentially via activity as a presynaptic scaffold protein (By similarity) Required for the induction of cell death mediated by TGF-beta and possibly by other apoptotic stimuli (PubMed:11146656, PubMed:15837787). Induces apoptosis through binding and inhibition of XIAP resulting in significant reduction in XIAP levels, leading to caspase activation and cell death (PubMed:15029247). Mediates the interaction between BCL2 and XIAP, thereby positively regulating the ubiquitination and degradation of BCL2 and promoting apoptosis (PubMed:29020630)","subcellular_location":"Mitochondrion; Nucleus","url":"https://www.uniprot.org/uniprotkb/O43236/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEPTIN4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SEPTIN4","total_profiled":1310},"omim":[{"mim_id":"621194","title":"SPERMATOGENIC FAILURE 99; SPGF99","url":"https://www.omim.org/entry/621194"},{"mim_id":"614779","title":"HETEROTAXY, VISCERAL, 6, AUTOSOMAL; HTX6","url":"https://www.omim.org/entry/614779"},{"mim_id":"614759","title":"CILIA- AND 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O. Berg (Myrtaceae).","date":"2019","source":"Natural product research","url":"https://pubmed.ncbi.nlm.nih.gov/31090448","citation_count":13,"is_preprint":false},{"pmid":"32996043","id":"PMC_32996043","title":"Euterpe oleracea Mart. (Açaí) attenuates experimental colitis in rats: involvement of TLR4/COX-2/NF-ĸB.","date":"2020","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32996043","citation_count":13,"is_preprint":false},{"pmid":"17644312","id":"PMC_17644312","title":"The pro-apoptotic ARTS/Sept4 protein is significantly reduced in post-mortem brains from schizophrenic patients.","date":"2007","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/17644312","citation_count":13,"is_preprint":false},{"pmid":"32025217","id":"PMC_32025217","title":"Septin4 Prevents PDGF-BB-induced HAVSMC Phenotypic Transformation, Proliferation and Migration by Promoting SIRT1-STAT3 Deacetylation and Dephosphorylation.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32025217","citation_count":12,"is_preprint":false},{"pmid":"25582427","id":"PMC_25582427","title":"Expression of Septin4 in Schistosoma japonicum-infected mouse livers after praziquantel treatment.","date":"2015","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/25582427","citation_count":12,"is_preprint":false},{"pmid":"18482221","id":"PMC_18482221","title":"Antioxidant and hepatoprotective effects of Cyathea phalerata Mart. (Cyatheaceae).","date":"2008","source":"Basic & clinical pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/18482221","citation_count":12,"is_preprint":false},{"pmid":"9392030","id":"PMC_9392030","title":"The arts in spiritual care.","date":"1997","source":"Seminars in oncology nursing","url":"https://pubmed.ncbi.nlm.nih.gov/9392030","citation_count":12,"is_preprint":false},{"pmid":"25154881","id":"PMC_25154881","title":"Deciphering the unusual HLA-A2/Melan-A/MART-1-specific TCR repertoire in humans.","date":"2014","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25154881","citation_count":12,"is_preprint":false},{"pmid":"34166151","id":"PMC_34166151","title":"Free to be: Experiences of arts-based relational caring in a community living and thriving with dementia.","date":"2021","source":"Dementia (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34166151","citation_count":12,"is_preprint":false},{"pmid":"23180367","id":"PMC_23180367","title":"Expression of Septin4 in human hepatic stellate cells LX-2 stimulated by LPS.","date":"2013","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/23180367","citation_count":11,"is_preprint":false},{"pmid":"37733173","id":"PMC_37733173","title":"Arts Therapy and Its Implications in Chronic Pain Management: A Narrative Review.","date":"2023","source":"Pain and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37733173","citation_count":11,"is_preprint":false},{"pmid":"32529277","id":"PMC_32529277","title":"Regulation of biofilm formation by marT in Salmonella Typhimurium.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32529277","citation_count":11,"is_preprint":false},{"pmid":"31766942","id":"PMC_31766942","title":"How Does Creative Arts Therapy Reduce Distress for Children With Cancer? A Metasynthesis of Extant Qualitative Literature.","date":"2019","source":"Journal of pediatric oncology nursing : official journal of the Association of Pediatric Oncology Nurses","url":"https://pubmed.ncbi.nlm.nih.gov/31766942","citation_count":11,"is_preprint":false},{"pmid":"30155717","id":"PMC_30155717","title":"Hexane partition from Annona crassiflora Mart. promotes cytotoxity and apoptosis on human cervical cancer cell lines.","date":"2018","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/30155717","citation_count":11,"is_preprint":false},{"pmid":"21351299","id":"PMC_21351299","title":"Antiproliferative activity of three methoxylated flavonoids isolated from Zeyheria montana Mart. (Bignoniaceae) leaves.","date":"2011","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/21351299","citation_count":11,"is_preprint":false},{"pmid":"34230460","id":"PMC_34230460","title":"Septin4 promotes cardiomyocytes apoptosis by enhancing the VHL-mediated degradation of HIF-1α.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34230460","citation_count":10,"is_preprint":false},{"pmid":"30221966","id":"PMC_30221966","title":"Arts-based psychiatric rehabilitation programs in the community: Perceptions of healthcare professionals.","date":"2018","source":"Psychiatric rehabilitation journal","url":"https://pubmed.ncbi.nlm.nih.gov/30221966","citation_count":10,"is_preprint":false},{"pmid":"20948439","id":"PMC_20948439","title":"Lovastatin inhibits T-cell proliferation while preserving the cytolytic function of EBV, CMV, and MART-1-specific CTLs.","date":"2010","source":"Journal of immunotherapy (Hagerstown, Md. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/20948439","citation_count":10,"is_preprint":false},{"pmid":"18243941","id":"PMC_18243941","title":"Time for Me: the arts as therapy in postnatal depression.","date":"2007","source":"Complementary therapies in clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/18243941","citation_count":10,"is_preprint":false},{"pmid":"33386578","id":"PMC_33386578","title":"Plastid genome evolution in Amazonian açaí palm (Euterpe oleracea Mart.) and Atlantic forest açaí palm (Euterpe edulis Mart.).","date":"2021","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33386578","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51641,"output_tokens":5694,"usd":0.120166,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14174,"output_tokens":5762,"usd":0.10746,"stage2_stop_reason":"end_turn"},"total_usd":0.227626,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"ARTS (Sept4_i2) is released from mitochondria upon pro-apoptotic stimuli and directly binds XIAP in vitro; binding is specific and required for pro-apoptotic function, as ARTS mutants that fail to bind XIAP also fail to induce apoptosis. ARTS binding to XIAP leads to decreased XIAP protein levels and caspase activation.\",\n      \"method\": \"In vitro binding assay with recombinant proteins, coimmunoprecipitation, cell-based apoptosis assays, mutagenesis of ARTS and related septins\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted direct binding in vitro with recombinant proteins, complemented by cell-based functional assays and mutagenesis showing binding is required for apoptotic activity\",\n      \"pmids\": [\"15029247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ARTS binds XIAP at the BIR1 domain (distinct from caspase-binding sites) and interacts with the E3 ligase Siah-1, acting as an adaptor to bridge Siah-1 to XIAP, thereby inducing XIAP ubiquitination and degradation. Cells lacking either Siah or ARTS have elevated steady-state XIAP levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, genetic knockdown/knockout of ARTS and Siah in cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying BIR1 as binding domain, E3 ligase interaction, and complementary loss-of-function data in cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21185211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ARTS forms a ternary complex with XIAP and Bcl-2 at the outer mitochondrial membrane upon apoptotic induction. ARTS binding to Bcl-2 involves the BH3 domain of Bcl-2; XIAP serves as an E3 ligase ubiquitinating Bcl-2 at Lysine 17, and ARTS is essential for this process. A Bcl-2 K17A mutant has increased stability and stronger anti-apoptotic potency. Bcl-2 ubiquitylation is reduced in both XIAP- and Sept4/ARTS-deficient MEFs.\",\n      \"method\": \"Co-immunoprecipitation (ternary complex), ubiquitylation assays, site-directed mutagenesis (K17A Bcl-2, BH3 domain), MEF knockout cells, mass spectrometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including mutagenesis, reciprocal Co-IP, ubiquitylation assays in knockout MEFs establishing mechanistic details\",\n      \"pmids\": [\"29020630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ARTS protein levels are kept low in healthy cells through constant ubiquitin-mediated proteasomal degradation. Upon pro-apoptotic stimuli, ARTS ubiquitination is inhibited, leading to increased ARTS levels, decreased Bcl-2 and Bcl-xL protein levels, cytochrome c release, and apoptosis.\",\n      \"method\": \"Ubiquitination assays, proteasome inhibitor treatments, overexpression and protein stability experiments in cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based ubiquitination assays with functional readouts, single lab with multiple methods\",\n      \"pmids\": [\"15837787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Parkin (E3-ubiquitin ligase) binds both ARTS (Sept4_i2) and Sept4_i1 but specifically ubiquitinates and degrades only ARTS via the ubiquitin-proteasome system. Parkin loss-of-function increases ARTS levels and promotes apoptosis; Parkin overexpression protects cells from ARTS-induced apoptosis. High ARTS levels are found in rat brains treated with 6-OHDA.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Parkin overexpression and knockdown, neuronal cell culture apoptosis assays, in vivo 6-OHDA rat model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, gain- and loss-of-function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22792159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of the mouse Sept4 gene (encoding ARTS) results in increased numbers of hematopoietic stem and progenitor cells, elevated XIAP protein, increased resistance to cell death, and accelerated tumor development in an Eμ-Myc background. These phenotypes are partially suppressed by inactivation of XIAP, placing ARTS upstream of XIAP in the apoptotic pathway.\",\n      \"method\": \"Sept4 knockout mice, Eμ-Myc tumor model, XIAP genetic inactivation (epistasis), FACS of hematopoietic stem/progenitor cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double knockout, in vivo tumor model, stem cell quantification; multiple orthogonal in vivo approaches\",\n      \"pmids\": [\"20952537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sept4/ARTS-deficient mice have elevated numbers of hair follicle stem cells (HFSCs) protected against apoptosis, display improved wound healing and hair follicle regeneration. Inactivation of XIAP, a direct ARTS target, abrogates these phenotypes, demonstrating ARTS acts via XIAP to regulate stem cell apoptosis and tissue regeneration.\",\n      \"method\": \"Sept4/ARTS knockout mice, lineage tracing, XIAP genetic inactivation, wound healing assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (ARTS KO + XIAP KO double mutant rescues phenotype), lineage tracing, multiple orthogonal methods\",\n      \"pmids\": [\"23788729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARTS is highly expressed in intestinal stem cell niche cells; its deletion protects Lgr5+ and Paneth cells from apoptosis, leading to augmented crypt proliferation, enhanced Wnt/β-catenin signaling, and massive cystic organoids. ARTS interacts with XIAP in intestinal crypt cells and deletion of XIAP abrogates Sept4/ARTS-/- phenotypes.\",\n      \"method\": \"Sept4/ARTS knockout mice, intestinal organoid culture, co-immunoprecipitation (ARTS-XIAP), XIAP genetic epistasis, Wnt/β-catenin signaling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO phenotype, organoid functional assay, XIAP epistasis, Co-IP; multiple orthogonal methods in single study\",\n      \"pmids\": [\"30389919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARTS is a p53 target gene: p53 transcriptionally activates the ARTS promoter via a p53-responsive DNA element. In turn, ARTS binds p53 protein and sequesters it at mitochondria, enhancing interaction between p53 and Bcl-XL, thereby promoting mitochondrial apoptosis. Ectopic ARTS augments DNA damage-induced apoptosis; ablation of ARTS impairs p53-induced apoptosis.\",\n      \"method\": \"Luciferase reporter assay (ARTS promoter), ChIP (p53 binding to ARTS promoter), co-immunoprecipitation (ARTS-p53, p53-Bcl-XL), ARTS knockdown/overexpression, γ-irradiation in mice\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, reciprocal Co-IP, reporter assay, in vivo irradiation, gain- and loss-of-function; multiple orthogonal methods in single study\",\n      \"pmids\": [\"33627621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Sept4 gene encodes two major isoforms (Sept4_i1/H5/PNUTL2 and Sept4_i2/ARTS) through a combination of two distinct promoters, differential splicing, and intron retention. ARTS is localized at mitochondria and promotes apoptosis, while Sept4_i1 is non-apoptotic; these structural differences explain their divergent biological activities.\",\n      \"method\": \"Molecular characterization (promoter analysis, splicing analysis), subcellular fractionation/immunolocalization\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of gene structure and isoform-specific localization, review synthesizing prior experimental data; single lab\",\n      \"pmids\": [\"21824006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WWP2 (a HECT-type E3 ubiquitin ligase) interacts with the GTPase domain of Septin4 and ubiquitinates Septin4 at K174, promoting its degradation via the ubiquitin-proteasome system. This inhibits the Septin4-PARP1 endothelial damage complex. Endothelial/myeloid-specific WWP2 knockout in mice aggravates oxidative stress-induced endothelial injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K174), WWP2 knockout mice (endothelial-specific), in vitro endothelial injury assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assays with mutagenesis, in vivo conditional KO; multiple orthogonal methods\",\n      \"pmids\": [\"31924572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Septin4 directly interacts with PARP1 (identified as a novel binding partner), and this interaction is enhanced under oxidative stress. Knockdown and overexpression of Septin4 modulate ROS production and apoptosis in endothelial cells under oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation (Septin4-PARP1), Septin4 knockdown and overexpression, ROS assays, apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP identifying novel binding partner, gain- and loss-of-function with functional readouts; single lab, single Co-IP method\",\n      \"pmids\": [\"29366480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT2 deacetylates Septin4 at lysine 174 (K174); hyperacetylation of K174 (mimicked by K174Q mutant) activates the cleaved-PARP1-cleaved-caspase3 pathway and exacerbates angiotensin II-induced hypertensive renal injury. Septin4-K174R (deacetylation mimic) rescues podocyte apoptosis. SIRT2 interacts with the Septin4 GTPase domain.\",\n      \"method\": \"Transgenic SIRT2 mice, SIRT2 knockout mice, septin4-K174Q and K174R mutant knock-in mice, co-immunoprecipitation, mass spectrometry, proteomic/acetyl-proteomics, Western blot\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-directed mutagenesis (K174Q/R), multiple transgenic/KO mouse models, Co-IP, mass spectrometry; mechanistic mutagenesis with in vivo validation\",\n      \"pmids\": [\"36786216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Septin4 modulates autophagy in vascular smooth muscle cells (VSMCs); overexpression of Septin4 reduces autophagy levels and decreases Ang-II-induced VSMC proliferation and migration. Blocking autophagy with chloroquine further restrains proliferation and migration in Septin4-overexpressing VSMCs, confirming Septin4 regulates these processes via autophagy.\",\n      \"method\": \"Septin4 overexpression in VSMCs, autophagy inhibition with chloroquine, proliferation and migration assays, in vivo Ang-II infusion in mice\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pharmacological epistasis (chloroquine), in vivo model; single lab, limited mechanistic depth on direct binding\",\n      \"pmids\": [\"32085901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Septin4 forms a complex with SIRT1 and STAT3 (co-immunoprecipitation), enhancing the interaction between SIRT1 and STAT3 and promoting SIRT1-regulated STAT3-K685 deacetylation and STAT3-Y705 dephosphorylation, thereby inhibiting PDGF-BB-induced HAVSMC proliferation, migration, and phenotypic transformation.\",\n      \"method\": \"Co-immunoprecipitation (Septin4-SIRT1-STAT3 complex), Septin4 knockdown and overexpression, phosphorylation and acetylation site analysis, VSMC functional assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying ternary complex, gain- and loss-of-function with specific post-translational modification readouts; single lab\",\n      \"pmids\": [\"32025217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Septin4 interacts with HIF-1α at the Septin4 GTPase domain and enhances the binding between HIF-1α and the E3 ubiquitin ligase VHL, promoting HIF-1α ubiquitin-mediated degradation. By reducing HIF-1α levels, Septin4 aggravates hypoxia-induced cardiomyocyte apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (Septin4-HIF-1α, HIF-1α-VHL), GTPase domain mapping, ubiquitination assays, cardiomyocyte hypoxia model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying novel binding partners, domain mapping, ubiquitination assays with functional apoptosis readout; single lab\",\n      \"pmids\": [\"34230460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function mutations in SEPTIN4 (c.A721T/p.R241* and c.C205T/p.R69*) in humans cause thin midpiece spermatozoa, annulus loss, disorganized mitochondrial sheath, and asthenoteratozoospermia. SEPT4 is required for SEPT-based annulus formation and correct localization of SEPTIN subunits and the anion transporter SLC26A8 at the sperm annulus.\",\n      \"method\": \"Human genetics (biallelic variant identification), immunofluorescence, immunoblotting (TOMM20, HSP60, SLC26A8), electron microscopy of sperm ultrastructure\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human loss-of-function variants with multiple orthogonal structural and localization assays confirming SEPT4's role in annulus formation and sperm midpiece integrity\",\n      \"pmids\": [\"36135717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Sept4/ARTS-/- mice, neutrophil apoptosis, macrophage efferocytosis, and macrophage reprogramming to pro-resolving phenotype are all impaired during resolution of inflammation (zymosan-induced peritonitis). ARTS overexpression in leukocytes in vitro promotes anti-inflammatory behavior, indicating ARTS acts upstream of XIAP to regulate apoptosis-dependent resolution of inflammation.\",\n      \"method\": \"Sept4/ARTS-/- mice, zymosan-induced peritonitis model, ARTS overexpression in leukocytes, cytokine measurements, efferocytosis assays\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with specific cellular phenotypes, in vitro gain-of-function; single lab, multiple readouts\",\n      \"pmids\": [\"32564202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Septin4_i1 induces apoptosis in hepatic stellate cells (LX-2) by upregulating PPAR-γ and reducing phosphorylated Akt and Bcl-2 expression. Cleaved-caspase-3 increases upon Septin4_i1 overexpression, and this effect is reversed by a PPAR-β/δ agonist (GW501516, which enhances Akt signaling) or a PPAR-γ antagonist (GW9662).\",\n      \"method\": \"Overexpression of Septin4_i1 in LX-2 cells, pharmacological inhibitor/agonist treatment, Western blot for PPAR-γ, Akt, Bcl-2, caspase-3\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pharmacological epistasis identifying PPAR-γ/Akt/Bcl-2 pathway; single lab, cell-line-based\",\n      \"pmids\": [\"25527525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A small molecule (A4) mimicking ARTS binds XIAP at a distinct pocket in the BIR3 domain (not the caspase-binding site, consistent with ARTS binding at BIR1 region), stimulates poly-ubiquitylation and UPS-mediated degradation of XIAP and Bcl-2 (but not cIAP1), activates caspase-9 and -3, and induces apoptosis. XIAP overexpression rescues cells from A4-induced death.\",\n      \"method\": \"Microscale thermophoresis (binding assay), ubiquitylation assays, caspase activation assays, XIAP overexpression rescue, proteome analysis of cancer cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biophysical binding assay, ubiquitylation assays, functional rescue; validates ARTS binding pocket in XIAP; single lab\",\n      \"pmids\": [\"32587235\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEPTIN4/ARTS (Sept4_i2) is a mitochondria-localized pro-apoptotic protein that, upon apoptotic stimulation, translocates to the cytosol and directly binds XIAP at its BIR1 domain, acting as an adaptor for the E3 ligase Siah-1 to ubiquitinate and degrade XIAP; it simultaneously brings XIAP and Bcl-2 into a ternary complex enabling XIAP-mediated ubiquitination and proteasomal degradation of Bcl-2 at K17; ARTS also binds and sequesters p53 at mitochondria to enhance p53-Bcl-XL interaction and promote mitochondrial apoptosis, while in living cells ARTS itself is kept at low levels by ubiquitin-proteasomal degradation via Parkin and WWP2 (the latter targeting K174), and by SIRT2-mediated deacetylation of K174, which modulates ARTS activity in podocytes; beyond its apoptotic role, Septin4 is an essential structural component of the sperm annulus (required for midpiece integrity and SLC26A8 localization), and interacts with PARP1, SIRT1-STAT3, and HIF-1α-VHL complexes to regulate endothelial injury, vascular smooth muscle cell behavior, and cardiomyocyte apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEPTIN4 encodes two functionally divergent isoforms generated by alternative promoters, splicing, and intron retention: the mitochondrial pro-apoptotic isoform Sept4_i2/ARTS and the non-apoptotic Sept4_i1 [#9]. ARTS is a tumor-suppressive antagonist of the inhibitor-of-apoptosis protein XIAP: upon pro-apoptotic stimulation it is released from mitochondria and binds XIAP directly at the BIR1 domain, a site distinct from the caspase-binding pockets [#0, #1]. Bound ARTS acts as an adaptor that bridges the E3 ligase Siah-1 to XIAP, driving XIAP ubiquitination and proteasomal degradation and thereby relieving caspase inhibition [#1]. ARTS additionally nucleates a ternary complex with XIAP and Bcl-2 in which XIAP ubiquitinates Bcl-2 at Lys17 to promote its degradation, and it binds and sequesters p53 at mitochondria to enhance the p53–Bcl-XL interaction; ARTS is itself a transcriptional target of p53 [#2, #8]. This ARTS–XIAP axis governs apoptosis-dependent control of stem cell pools and tissue homeostasis: Sept4/ARTS loss elevates XIAP, protects hematopoietic, hair-follicle, and intestinal stem cells from death, accelerates tumorigenesis, and impairs inflammation resolution, with all phenotypes reverted by XIAP inactivation [#5, #6, #7, #17]. In healthy cells ARTS is held at low levels by constitutive ubiquitin–proteasome turnover, mediated by Parkin and by WWP2-catalyzed ubiquitination at Lys174, with SIRT2-dependent deacetylation of the same residue modulating its pro-apoptotic activity in podocytes [#3, #4, #10, #12]. Beyond apoptosis, Septin4 is an essential structural component of the sperm annulus required for midpiece integrity and SLC26A8 localization, and biallelic loss-of-function SEPTIN4 mutations cause asthenoteratozoospermia in humans [#16]. In the vasculature and myocardium Septin4 binds PARP1, SIRT1–STAT3, and the HIF-1α–VHL machinery to regulate endothelial injury, smooth muscle cell behavior, and cardiomyocyte apoptosis [#11, #14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that the SEPTIN4 isoform ARTS is a mitochondrial pro-apoptotic protein that acts directly on XIAP, defining its core molecular target.\",\n      \"evidence\": \"In vitro binding with recombinant proteins, Co-IP, cell-based apoptosis assays, and mutagenesis in cell lines\",\n      \"pmids\": [\"15029247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the binding domain on XIAP\", \"Mechanism of how binding lowers XIAP levels left undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed why ARTS is dormant in living cells — it is held at low levels by constitutive ubiquitin-proteasome degradation that is relieved upon apoptotic signaling.\",\n      \"evidence\": \"Ubiquitination assays, proteasome inhibition, and protein stability experiments in cell lines\",\n      \"pmids\": [\"15837787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The responsible E3 ligase was not identified here\", \"Signal that inhibits ARTS ubiquitination upon apoptotic induction unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the molecular mechanism of XIAP destruction, showing ARTS binds the BIR1 domain and bridges the E3 ligase Siah-1 to drive XIAP ubiquitination.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, and loss-of-function in ARTS- and Siah-deficient cells\",\n      \"pmids\": [\"21185211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the ARTS–Siah-1–XIAP complex not defined\", \"No structural model of the BIR1 interface\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed ARTS genetically upstream of XIAP in vivo, demonstrating it is a tumor suppressor that restrains hematopoietic stem cell survival.\",\n      \"evidence\": \"Sept4 knockout mice, Eµ-Myc tumor model, XIAP epistasis double knockout, FACS of stem/progenitor cells\",\n      \"pmids\": [\"20952537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions to tumor suppression not dissected\", \"Does not address non-XIAP targets\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Explained the divergent biology of the locus by characterizing two isoforms with distinct promoters, splicing, and subcellular localization.\",\n      \"evidence\": \"Promoter and splicing analysis plus subcellular fractionation/immunolocalization\",\n      \"pmids\": [\"21824006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of Sept4_i1 left largely undefined\", \"Synthesis of prior data rather than new mechanism\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Parkin as an E3 ligase that selectively degrades ARTS, linking ARTS turnover to a neuronal survival pathway.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, Parkin gain/loss-of-function, neuronal apoptosis assays, and a 6-OHDA rat model\",\n      \"pmids\": [\"22792159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on ARTS not mapped\", \"Relationship between Parkin and other ARTS ligases unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the ARTS–XIAP axis to adult tissue regeneration, showing ARTS controls hair follicle stem cell apoptosis via XIAP.\",\n      \"evidence\": \"Sept4/ARTS knockout mice, lineage tracing, XIAP epistasis, wound healing assays\",\n      \"pmids\": [\"23788729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals triggering ARTS in stem cells unknown\", \"Whether effect is cell-autonomous within the niche not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded ARTS function beyond XIAP degradation, showing it nucleates an XIAP–Bcl-2 ternary complex enabling Bcl-2 ubiquitination at K17.\",\n      \"evidence\": \"Co-IP of the ternary complex, ubiquitylation assays, K17A/BH3 mutagenesis, knockout MEFs, mass spectrometry\",\n      \"pmids\": [\"29020630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial/temporal coordination with XIAP degradation not resolved\", \"Bcl-xL regulation mechanism less defined than Bcl-2\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated ARTS restrains intestinal stem cell survival and Wnt signaling, with phenotypes XIAP-dependent.\",\n      \"evidence\": \"Knockout mice, intestinal organoids, ARTS-XIAP Co-IP, XIAP epistasis, Wnt/β-catenin assays\",\n      \"pmids\": [\"30389919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between ARTS loss and Wnt activation indirect\", \"Direct ARTS effectors in crypt cells beyond XIAP unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PARP1 as a novel Septin4 partner relevant to oxidative endothelial stress.\",\n      \"evidence\": \"Co-IP, Septin4 knockdown/overexpression, ROS and apoptosis assays in endothelial cells\",\n      \"pmids\": [\"29366480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal/structural validation\", \"Functional consequence of the Septin4-PARP1 complex on PARP1 activity unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined WWP2 as a HECT E3 ligase that ubiquitinates Septin4 at K174 to suppress the Septin4-PARP1 endothelial damage complex.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, K174 mutagenesis, endothelial-specific WWP2 knockout mice\",\n      \"pmids\": [\"31924572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between WWP2 and Parkin in Septin4 turnover not addressed\", \"Isoform specificity of K174 ubiquitination not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed Septin4 promotes formation of a SIRT1–STAT3 complex to suppress vascular smooth muscle cell proliferation through STAT3 deacetylation/dephosphorylation.\",\n      \"evidence\": \"Reciprocal Co-IP of ternary complex, gain/loss-of-function, STAT3 PTM analysis, VSMC functional assays\",\n      \"pmids\": [\"32025217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffolding role of Septin4 in the complex unclear\", \"Single-lab finding without structural mapping\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked Septin4 to autophagy regulation in vascular smooth muscle cells controlling proliferation and migration.\",\n      \"evidence\": \"Septin4 overexpression, chloroquine epistasis, proliferation/migration assays, in vivo Ang-II infusion\",\n      \"pmids\": [\"32085901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular link between Septin4 and the autophagy machinery\", \"Mechanism of autophagy suppression undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a role for ARTS in resolution of inflammation through control of neutrophil apoptosis and macrophage efferocytosis.\",\n      \"evidence\": \"Sept4/ARTS knockout mice, zymosan peritonitis, leukocyte overexpression, efferocytosis and cytokine assays\",\n      \"pmids\": [\"32564202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether macrophage reprogramming is XIAP-dependent not directly tested\", \"Cell-intrinsic vs extrinsic contributions not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Validated the ARTS-binding pocket on XIAP pharmacologically, showing a small molecule recapitulates ARTS-driven XIAP/Bcl-2 degradation and apoptosis.\",\n      \"evidence\": \"Microscale thermophoresis, ubiquitylation and caspase assays, XIAP rescue, cancer cell proteome analysis\",\n      \"pmids\": [\"32587235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Compound binds BIR3, leaving exact correspondence to ARTS BIR1 site partly inferential\", \"Selectivity in vivo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected ARTS to the p53 axis as both a transcriptional target and a mitochondrial p53-sequestering factor that promotes apoptosis.\",\n      \"evidence\": \"Luciferase reporter, ChIP, reciprocal Co-IP, gain/loss-of-function, in vivo irradiation\",\n      \"pmids\": [\"33627621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of ARTS-p53 binding unknown\", \"Interplay with the XIAP-degradation function not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed Septin4 enhances HIF-1α–VHL binding to drive HIF-1α degradation, aggravating cardiomyocyte apoptosis under hypoxia.\",\n      \"evidence\": \"Co-IP, GTPase domain mapping, ubiquitination assays, cardiomyocyte hypoxia model\",\n      \"pmids\": [\"34230460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contact residues between Septin4 and HIF-1α undefined\", \"Single-lab finding without in vivo validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a structural, apoptosis-independent role for SEPTIN4, establishing it as essential for the sperm annulus and a cause of human asthenoteratozoospermia.\",\n      \"evidence\": \"Human biallelic loss-of-function variants, immunofluorescence, immunoblotting, electron microscopy of sperm\",\n      \"pmids\": [\"36135717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of SLC26A8 mislocalization not detailed\", \"How structural and apoptotic functions are partitioned between isoforms unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an acetylation switch on Septin4-K174 controlled by SIRT2 that tunes its pro-apoptotic activity in hypertensive renal injury.\",\n      \"evidence\": \"Transgenic/knockout SIRT2 mice, K174Q/R knock-in mice, Co-IP, mass spectrometry, acetyl-proteomics\",\n      \"pmids\": [\"36786216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between K174 acetylation and K174 ubiquitination by WWP2 not directly resolved\", \"Generalizability beyond podocytes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the apoptotic ARTS isoform and the structural/scaffolding Septin4 functions are coordinated at the protein level, and whether the cytoplasmic vascular/cardiac partner interactions (PARP1, SIRT1-STAT3, HIF-1α-VHL) involve canonical septin filament assembly, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ARTS-XIAP or ARTS-p53 complexes\", \"Isoform-specific contributions to vascular and cardiac phenotypes not dissected\", \"Relationship between septin polymerization and the apoptotic adaptor function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 8, 14, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 8, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 5, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 4, 10, 12, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\"ARTS-XIAP-Siah-1 complex\", \"ARTS-XIAP-Bcl-2 ternary complex\", \"Septin4-SIRT1-STAT3 complex\", \"sperm annulus\"],\n    \"partners\": [\"XIAP\", \"SIAH1\", \"BCL2\", \"TP53\", \"PARK2\", \"WWP2\", \"SIRT2\", \"PARP1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}