{"gene":"SEPTIN7","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1991,"finding":"The CDC3 gene product (yeast ortholog of SEPT7) localizes to the ring of 10-nm filaments at the mother-bud neck in S. cerevisiae, as shown by immunofluorescence with antibodies generated against CDC3 fusion proteins. CDC3 protein assembles into a ring at the budding site before bud emergence and remains organized there after cytokinesis, establishing it as a structural constituent of septin filaments.","method":"Immunofluorescence with polyclonal antibodies raised against CDC3 fusion proteins in wild-type and mutant yeast cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence, replicated across multiple genetic backgrounds and time points, consistent with prior CDC12 data","pmids":["1993729"],"is_preprint":false},{"year":1999,"finding":"The yeast SUMO-1 homolog Smt3 is conjugated to Cdc3 (yeast SEPT7 ortholog) at the mother-bud neck septin rings, as demonstrated by immunoprecipitation. Loss of Smt3 conjugation (in a ubc9-1 mutant) results in disappearance of septin rings and reduction of the Cdc3-Smt3 conjugate. The conjugate disappears around the time of cytokinesis, indicating SUMO modification of Cdc3 regulates septin ring dynamics.","method":"Immunoprecipitation, indirect immunofluorescence, genetic analysis using ubc9-1 mutant","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP plus localization with functional consequence in a defined mutant background, single lab","pmids":["10364461"],"is_preprint":false},{"year":2002,"finding":"The yeast septin Cdc3 is phosphorylated near its C-terminus by the Cdc28 (CDK1) kinase in a cell-cycle-dependent manner. Mutation of the Cdc28-dependent phosphorylation sites impairs disassembly of the old septin ring inherited at mitosis; G1 cyclin function is required for efficient ring disassembly, placing CDK-mediated Cdc3 phosphorylation as a regulator of septin ring turnover at G1.","method":"Phospho-site mutagenesis, immunofluorescence analysis of septin ring dynamics in wild-type and cln mutants","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of phosphorylation sites plus cell-cycle genetic analysis, single lab","pmids":["12429908"],"is_preprint":false},{"year":2004,"finding":"Mammalian SEPT7 is a component of a septin complex with SEPT9b and SEPT11 in rat fibroblasts. Affinity purification with anti-SEPT7 antibody co-purified SEPT2, SEPT7, SEPT8, SEPT9b, and SEPT11. SEPT7, SEPT9b, and SEPT11 co-localize along stress fibers and directly bind each other through their N- or C-terminal divergent regions. Co-expression experiments in COS7 cells reveal combination-dependent filament elongation, bundling, or disruption.","method":"Anti-SEPT7 antibody affinity purification, immunoprecipitation, immunofluorescence, transient co-expression in COS7 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — affinity purification plus reciprocal immunoprecipitation plus cell imaging, multiple orthogonal methods in one study","pmids":["15485874"],"is_preprint":false},{"year":2007,"finding":"SEPT7 localizes to the bases of filopodia and dendritic branch points in developing hippocampal neurons and to the bases of dendritic spines in mature neurons. Downregulation of SEPT7 impairs dendritic branching and causes elongated spine morphology. SEPT5 and SEPT11 co-localize with and co-immunoprecipitate with SEPT7, indicating existence of a SEPT5/7/11 complex in neurons.","method":"Immunofluorescence, siRNA knockdown, co-immunoprecipitation in hippocampal neurons","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, direct localization experiments with functional consequences (knockdown phenotype), multiple orthogonal methods","pmids":["17935997"],"is_preprint":false},{"year":2008,"finding":"SEPT7 directly interacts with the C-terminal domain of the kinetochore motor CENP-E, as demonstrated by GST pull-down and yeast two-hybrid assays. SEPT7 filaments distribute along the mitotic spindle and terminate at the kinetochore. siRNA-mediated depletion of SEPT7 abolishes kinetochore localization of CENP-E, reduces kinetochore tension, activates the spindle checkpoint (Mad2, BubR1), and causes chromosome mis-segregation; all phenotypes are rescued by exogenous GFP-SEPT7.","method":"GST pull-down, yeast two-hybrid, immunofluorescence, siRNA knockdown with rescue experiment in HeLa and MDCK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro pull-down plus yeast two-hybrid plus cell-based siRNA with defined phenotype and rescue, multiple orthogonal methods","pmids":["18460473"],"is_preprint":false},{"year":2012,"finding":"SEPT7 forms a complex with CD2AP and nephrin in podocytes and co-immunoprecipitates with VAMP2. Filamentous localization of SEPT7 depends on CD2AP and intact actin organization. siRNA-mediated depletion of SEPT7 or pharmacological disruption of septin assembly with forchlorfenuron facilitates glucose uptake into podocytes and increases VAMP2 interaction with nephrin and syntaxin 4, indicating SEPT7 hinders GLUT4 storage vesicle (GSV) trafficking.","method":"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, immunofluorescence, 2-deoxy-D-glucose uptake assay in cultured podocytes","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus functional uptake assay plus localization with functional consequence, multiple orthogonal methods","pmids":["22809625"],"is_preprint":false},{"year":2012,"finding":"SEPT7 localizes to the meiotic spindle from pro-MI to MII stages in mouse oocytes. Knockdown of SEPT7 causes abnormal spindles and impairs extrusion of the first polar body. Overexpressed Myc-SEPT7 localizes to spindles and plasma membrane; overexpression weakens spindle α-tubulin fluorescence intensity and disrupts chromosome alignment and polar body extrusion, indicating SEPT7 regulates microtubule dynamics during meiosis.","method":"Immunofluorescence, siRNA microinjection knockdown, mRNA overexpression in mouse oocytes","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization plus loss- and gain-of-function with defined phenotypic readouts, single lab","pmids":["22895176"],"is_preprint":false},{"year":2014,"finding":"Genetic deletion of SEPT7 in mouse fibroblasts causes multinucleation due to failure of cytokinesis, associated with hyperacetylation/stabilization of microtubules and stalled midbody abscission. Supplementation with the microtubule-depolymerizing protein stathmin rescues cytokinesis failure in SEPT7-null fibroblasts. Knockdown of stathmin sensitizes a hematopoietic cell line to the septin inhibitor forchlorfenuron, establishing that septin-dependent cytokinesis requires microtubule destabilization via stathmin.","method":"Conditional genetic knockout (SEPT7-floxed mice), live-cell imaging, stathmin supplementation rescue, siRNA knockdown, forchlorfenuron treatment","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined phenotype, mechanistic rescue by stathmin, multiple cell types and orthogonal approaches","pmids":["25122120"],"is_preprint":false},{"year":2014,"finding":"SEPT6 and SEPT7 complexes bound to F-actin regulate multivesicular body (MVB) biogenesis by binding AP-3 (an endosomal adapter complex), modulating AP-3 membrane interactions and motility of AP-3-positive endosomes, and influencing ESCRT-I membrane interaction during cargo sorting. This coordination requires the E3 ubiquitin ligase LRSAM1.","method":"Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy of endosomal dynamics","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus cell-based functional readout, single lab with multiple methods","pmids":["25380047"],"is_preprint":false},{"year":2016,"finding":"SEPT7 acts as a negative regulator ('molecular brake') of Orai channel-mediated Ca²⁺ entry in Drosophila neurons. Lowering SEPT7 levels results in store-independent dOrai-mediated Ca²⁺ entry and elevated cytosolic Ca²⁺ at rest. Overexpression of SEPT7 reduces both store-operated Ca²⁺ entry (SOCE) and flight duration in vivo, demonstrating that SEPT7 modulates Orai channel function and neural circuit activity.","method":"Genetic knockdown and overexpression in Drosophila neurons, Ca²⁺ imaging, in vivo flight assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (KD and OE) with in vivo and in vitro functional readouts, replicated across multiple assays","pmids":["27225060"],"is_preprint":false},{"year":2016,"finding":"SEPT7 forms a complex with nonmuscle myosin heavy chain IIA (NMHC-IIA/MYH9) and SNAP23. Insulin decreases SEPT7 levels and increases NM-IIA activity in the SNAP23 complex. Knockdown of SEPT7 increases NM-IIA activity (measured by myosin regulatory light chain phosphorylation) in the SNAP23 complex and thereby facilitates GLUT4 storage vesicle docking and fusion with the plasma membrane, indicating SEPT7 hinders GSV fusion by suppressing NM-IIA activity.","method":"Co-immunoprecipitation, siRNA knockdown, Western blot for myosin light chain phosphorylation, glucose uptake assay in podocytes","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional assay with defined molecular mechanism, single lab","pmids":["28011197"],"is_preprint":false},{"year":2016,"finding":"GTPase domain-driven dimerization of SEPT7 is dispensable for its essential role in fibroblast cytokinesis. SEPT7 mutants with altered GTPase domain-dependent homo- or hetero-polymerization, GTP-binding, or GTPase activity can still rescue multinucleation in Sept7-null fibroblasts, indicating that well-defined native filament assembly via GTPase domain dimerization is not required for SEPT7's cytokinetic function.","method":"Conditional genetic knockout fibroblast system with doxycycline-inducible SEPT7 mutant rescue, biochemical analysis of GTPase mutants","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — genetic rescue system with biochemically characterized mutants, single lab","pmids":["26818767"],"is_preprint":false},{"year":2017,"finding":"The kinase TAOK2 directly phosphorylates SEPT7 at an evolutionarily conserved C-terminal residue (identified by chemical-genetics and mass spectrometry). This phosphorylation induces translocation of SEPT7 into the dendritic spine head, where SEPT7 associates with and stabilizes the scaffolding protein PSD95, promoting dendritic spine maturation and compartmentalization of NMDA receptor-mediated calcium influx.","method":"Chemical-genetic kinase labeling, mass spectrometry, phospho-site mutagenesis, live-cell imaging, co-immunoprecipitation in neurons","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — chemical-genetics plus MS identification plus mutagenesis plus functional rescue, multiple orthogonal methods in one rigorous study","pmids":["28065648"],"is_preprint":false},{"year":2018,"finding":"SEPT7 binds to the CALB2 (calretinin) gene promoter in a butyrate-dependent manner and acts as a transcriptional repressor of calretinin expression in malignant mesothelioma cells. Overexpression of SEPT7 decreases calretinin levels; conversely, calretinin overexpression decreases SEPT7 levels. SEPT7 and calretinin directly interact, as shown by co-immunoprecipitation, and co-localize in the cleavage furrow and midbody during cytokinesis.","method":"DNA-binding assays, peptide shotgun-mass spectrometry, dual-luciferase reporter assays, chromatin immunoprecipitation, lentiviral overexpression/knockdown, co-immunoprecipitation, immunofluorescence","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (DNA binding, reporter assay, co-IP, imaging), single lab","pmids":["29699512"],"is_preprint":false},{"year":2019,"finding":"High-resolution crystal structures of the SEPT7 GTPase domain complexed with GDP reveal coordination details of the magnesium ion and the molecular basis for interactions at the G-interface. A structural motif based on an antiparallel β-bridge at the G-interface rationalizes why SEPT7 (unlike some other septins) does not undergo nucleotide-dependent β-strand slippage, providing insight into filament assembly mechanisms.","method":"X-ray crystallography (two high-resolution structures of SEPT7 GTPase domain-GDP complex)","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structures with structural analysis, single lab but rigorous method","pmids":["31009756"],"is_preprint":false},{"year":2020,"finding":"SEPT7 interacts with KIF20A in the intercellular bridge of dividing neural progenitor cells (NPCs). Knockdown of SEPT7 displaces KIF20A from the midbody and triggers precocious neuronal differentiation. NPC-specific inducible knockout of Sept7 causes early cell cycle exit, precocious neuronal differentiation, and ventriculomegaly without a noticeable cytokinesis defect, indicating SEPT7 maintains the proliferative state of NPCs through KIF20A-mediated mechanisms.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, conditional inducible knockout mouse model, cortical phenotype analysis","journal":"Cerebral cortex (New York, N.Y. : 1991)","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP establishing interaction, in vivo knockout with defined phenotype, knockdown with mechanistic displacement of KIF20A, multiple orthogonal approaches","pmids":["31813992"],"is_preprint":false},{"year":2020,"finding":"SEPT7 prevents constitutive Ca²⁺ entry through Orai channels in human neural progenitor cells (hNPCs) and differentiated neurons. The N-terminal polybasic region of SEPT7, known to interact with membrane phospholipids, is essential for this inhibitory function (whereas the GTPase domain of dSEPT7 is dispensable). SEPT7 knockdown causes reorganization of Orai1 and STIM1 near the plasma membrane, supporting a model where SEPT7-containing heteromers prevent premature STIM-Orai complex activation.","method":"siRNA knockdown, Ca²⁺ imaging, domain-deletion analysis, TIRF/confocal microscopy of Orai1 and STIM1 localization in hNPCs","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion experiments plus imaging with functional Ca²⁺ readout, single lab","pmids":["32682163"],"is_preprint":false},{"year":2020,"finding":"SEPT7 localizes to the centrosome, and depletion of SEPT7 causes aberrant mitotic spindle pole formation and disorganized microtubule nucleation. SEPT7 forms a complex with p150glued (a centriole subdistal appendage component), and SEPT7 depletion reduces the abundance of p150glued. Overexpression of p150glued reverses the microtubule nucleation defects caused by SEPT7 deficiency, placing SEPT7 upstream of p150glued in microtubule array organization.","method":"siRNA knockdown, co-immunoprecipitation, immunofluorescence, rescue by p150glued overexpression, zebrafish embryo experiments","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional rescue establishes pathway position, single lab with multiple methods","pmids":["32869310"],"is_preprint":false},{"year":2021,"finding":"Protein kinase A (PKA) phosphorylates SEPT7 at Thr197, disrupting septin filament dynamics and primary cilia formation. Treatment with cAMP or overexpression of PKA catalytic subunit induces SEPT7 Thr197 phosphorylation. Constitutive phosphorylation at Thr197 reduces SEPT7-SEPT7 interaction but does not affect SEPT7-SEPT6-SEPT2 or SEPT4 interaction. SEPT7 interacts with PKACA2 via its GTP-binding domain.","method":"Phospho-site mutagenesis, co-immunoprecipitation, cAMP/PKA overexpression, immunofluorescence of septin filaments and primary cilia","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis plus co-IP plus functional ciliogenesis readout, single lab","pmids":["33572403"],"is_preprint":false},{"year":2021,"finding":"Loss of SEPT7 in Purkinje neurons rescues motor coordination deficits and aberrant climbing fiber innervation caused by STIM1 knockout. Loss of SEPT7 (one or two copies) in STIM1-knockout Purkinje neurons restores expression of a subset of genes including neuron projection development genes and normalizes CF-PN innervation, establishing that SEPT7 acts downstream of STIM1-dependent Ca²⁺ signaling in cerebellar circuit function.","method":"Conditional knockout mouse models (STIM1 and SEPT7), gene expression analysis, synapse morphology, rotarod behavioral testing","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo with behavioral and molecular readouts, single lab","pmids":["34993201"],"is_preprint":false},{"year":2022,"finding":"14-3-3 proteins (specifically 14-3-3 gamma) interact with SEPT7 in a phosphorylation-dependent manner, specifically when SEPT7 is phosphorylated at T426 (the TAOK2 phosphorylation site). 14-3-3 gamma is enriched in mature dendritic spine heads. Expression of a 14-3-3 antagonist significantly decreases phospho-SEPT7 levels in neurons, indicating that 14-3-3 binding protects phosphorylated SEPT7 from dephosphorylation.","method":"Phosphopeptide pulldown, co-immunoprecipitation, immunofluorescence in neurons, 14-3-3 antagonist expression","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphopeptide pulldown plus co-IP plus functional antagonist experiment, single lab with two orthogonal methods","pmids":["35601601"],"is_preprint":false},{"year":2022,"finding":"Conditional knockdown of Septin7 in mice causes hunchback phenotype with skeletal deformities, reduced in vivo and in vitro muscle force, and disorganized mitochondrial networks. Knockout of Septin7 in C2C12 cells abolishes cell division. Knockdown in C2C12 cells impairs myotube differentiation. Septin7 expression transiently increases following muscle injury, suggesting a role in muscle regeneration and development.","method":"Conditional knockout/knockdown mouse model, C2C12 cell knockout, immunofluorescence, force measurement, confocal microscopy","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with multiple defined phenotypic readouts plus cell-based experiments, multiple orthogonal approaches","pmids":["35929607"],"is_preprint":false},{"year":2022,"finding":"SEPT7 deletion in macrophages (via Lyz2-Cre) causes constitutive double-nucleation indicating a cytokinesis defect, but does not impair phagocytic function or LPS-stimulated TNF production. In AT2 cells, SEPT7 deletion dramatically suppresses oncogenic Kras-G12D-driven lung tumorigenesis, with control mice dying in 3-5 weeks while SEPT7-deficient animals survived 11+ weeks.","method":"Conditional genetic knockout (Lyz2-Cre × SEPT7-floxed), phagocytosis assay, TNF ELISA, histopathology, survival analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic deletion with defined cellular phenotypes (cytokinesis defect, tumor suppression), single lab","pmids":["35071236"],"is_preprint":false},{"year":2013,"finding":"SEPT7 forms a complex with N-cadherin in endothelial cells, and this complex is recruited by C. albicans Als3 and Ssa1 invasins. N-cadherin acts as a link between SEPT7 and the fungus; knockdown of N-cadherin reduces SEPT7 recruitment. SEPT7 knockdown decreases N-cadherin accumulation around C. albicans and significantly inhibits endocytosis of the organism. Intact actin microfilaments are required for SEPT7-N-cadherin association.","method":"Confocal microscopy, affinity purification, siRNA knockdown, cytochalasin D actin depolymerization","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification plus siRNA with defined endocytosis readout, single lab with multiple methods","pmids":["24345743"],"is_preprint":false},{"year":2013,"finding":"SEPT3 directly binds to SEPT5 and SEPT7 and forms a heteromeric complex at nerve terminals in mature neurons. In Sept3-null mice, expression of other septins including SEPT7 is unaltered, and SEPT3 is dispensable for normal neuronal development.","method":"Direct binding assay, co-immunoprecipitation, immunofluorescence in primary neurons, Sept3 knockout mouse analysis","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus co-IP establishing complex membership, single lab","pmids":["17564677"],"is_preprint":false},{"year":2024,"finding":"SEPT7 interacts with Numb in C2C12 myotubes (identified by proteomics of Numb immunoprecipitates). Immunofluorescence reveals partial overlap of Numb and SEPT7 in myofibers. Conditional knockout of Numb causes disorganization of SEPT7 staining in myofibers, indicating Numb-SEPT7 interactions are critical for sarcomere structural organization.","method":"Co-immunoprecipitation proteomics, immunofluorescence, conditional knockout mouse model","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP and in vivo disorganization phenotype, single lab","pmids":["38695862"],"is_preprint":false},{"year":2024,"finding":"ECM-mediated integrin activation regulates spatially distinct SEPT7 structures at focal adhesions (FAs) in fibroblasts. In perinuclear regions, ECM binding stabilizes SEPT7 bundles at the back of FAs; in peripheral FAs, high integrin activation promotes elongation of SEPT7 structures. Ventral SEPT7 structures are required for FA elongation, stabilization, and fibroblast mechanosensitivity.","method":"Total internal reflection fluorescence (TIRF) microscopy, siRNA knockdown, integrin activation manipulation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence via TIRF, single lab with defined phenotypic readout","pmids":["39650732"],"is_preprint":false},{"year":2024,"finding":"Blue light-induced inhibition of an engineered SEPT7-LOV2 hybrid protein in NK92 cells and CD8+ T cells induces extended cell protrusions and cell polarization, enhancing transmigration through confining spaces and improving penetration into tumor spheroids. This demonstrates that inhibiting SEPT7 function promotes immune cell infiltration by enhancing cell motility.","method":"Optogenetic protein engineering, live-cell imaging, transmigration assay, tumor spheroid infiltration assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered optogenetic system with defined functional readout, single study with multiple cell types","pmids":["39441641"],"is_preprint":false},{"year":2013,"finding":"SEPT7 (via Sept7 variant 4) suppresses Bax-mediated apoptosis in yeast and also confers resistance to copper-mediated cell death in a caspase-independent manner. The yeast SEPT7 ortholog CDC10 similarly protects against copper toxicity and Bax expression. SEPT7 was unable to rescue the cell size increase of cdc10Δ yeast, indicating distinct functions for the anti-apoptotic versus cytoskeletal roles.","method":"Heterologous expression screen in yeast, cell viability assay, caspase-deficient (mca1Δ) strain analysis","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast expression system with viability readout, indirect assay for apoptosis suppression, single lab","pmids":["24055994"],"is_preprint":false},{"year":2016,"finding":"SEPT2 and SEPT7 depletion in MDA-MB-231 breast cancer cells inhibits migration and invasion, while overexpression enhances these behaviors. MEK/ERK activation is positively correlated with SEPT2 and SEPT7 protein levels, and MEK inhibitor U0126 normalizes increased invasiveness in SEPT7-overexpressing cells, placing SEPT7 upstream of MEK/ERK in regulating cancer cell invasion.","method":"siRNA knockdown, forced overexpression, Transwell migration/invasion assays, MEK inhibitor treatment, Western blot for MAPK signaling","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell-based knockdown/overexpression with pathway inhibitor, single lab, correlation-based pathway placement","pmids":["27557506"],"is_preprint":false},{"year":2018,"finding":"SEPT7 interacts with DOCK8 in primary equine lymphocytes, as identified by interaction proteomics. DOCK8 expression and its interaction network are significantly altered in equine recurrent uveitis (autoimmune disease), and ILK is identified as a DOCK8 interactor in lymphocytes.","method":"Interaction proteomics (immunoprecipitation-mass spectrometry), Western blot validation","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP/proteomics experiment in primary cells, single lab, no mechanistic follow-up for SEPT7-DOCK8 interaction","pmids":["30120291"],"is_preprint":false}],"current_model":"SEPT7 is an essential, ubiquitously expressed GTP-binding cytoskeletal protein that serves as the central organizing subunit of all mammalian hetero-oligomeric septin complexes (including SEPT2/6/7/9/11 hexamers and octamers); it localizes to stress fibers, the cleavage furrow and midbody during cytokinesis (where it promotes microtubule destabilization via stathmin), to centrosomes (where it maintains p150glued abundance for microtubule nucleation), to the base of dendritic spines and branch points in neurons (where phosphorylation by TAOK2 at a conserved C-terminal residue drives spine maturation by stabilizing PSD95, an effect protected by 14-3-3 binding), and to focal adhesions in fibroblasts; SEPT7 acts as a negative regulator of Orai channel-mediated Ca²⁺ entry through its N-terminal polybasic phospholipid-binding region, stabilizes kinetochore localization of CENP-E by direct interaction to ensure chromosome segregation, hinders GLUT4 vesicle docking by suppressing nonmuscle myosin IIA activity in the SNAP23 complex, and can also function as a transcriptional repressor at the CALB2 promoter."},"narrative":{"mechanistic_narrative":"SEPTIN7 is the central organizing subunit of mammalian hetero-oligomeric septin complexes and functions as a GTP-binding cytoskeletal scaffold that couples membrane and microtubule/actin dynamics to cell division, neuronal architecture, and Ca²⁺ signaling [PMID:15485874, PMID:31009756]. From its earliest characterization as the yeast CDC3 ortholog forming the mother-bud neck filament ring, the protein has served as a structural constituent of septin filaments whose assembly and turnover are controlled by post-translational modification, including SUMO conjugation and cell-cycle-dependent CDK phosphorylation [PMID:1993729, PMID:10364461, PMID:12429908]. In mammalian cells SEPT7 assembles into combinatorial filaments with partners such as SEPT2, SEPT9b, and SEPT11 along stress fibers, and its essential role in cytokinesis operates through microtubule destabilization: SEPT7 loss stabilizes/hyperacetylates microtubules and stalls midbody abscission, a defect rescued by the depolymerizing factor stathmin [PMID:15485874, PMID:25122120]. This cytokinetic function is genetically separable from GTPase-domain-driven filament dimerization, which is dispensable for rescue of multinucleation [PMID:26818767]. During mitosis SEPT7 directly binds the kinetochore motor CENP-E to ensure its kinetochore localization, chromosome alignment, and satisfaction of the spindle checkpoint, and organizes centrosomal microtubule nucleation by maintaining p150glued abundance [PMID:18460473, PMID:32869310]. In the nervous system, SEPT7 localizes to the bases of dendritic branch points and spines and controls spine maturation: TAOK2 phosphorylates a conserved C-terminal residue (T426) to drive SEPT7 into spine heads where it stabilizes PSD95, an event protected from dephosphorylation by 14-3-3 gamma binding [PMID:17935997, PMID:28065648, PMID:35601601]. SEPT7 acts as a negative regulator of Orai-channel-mediated Ca²⁺ entry through its membrane-phospholipid-binding N-terminal polybasic region, preventing premature STIM-Orai activation, and functions downstream of STIM1 in cerebellar circuit wiring [PMID:27225060, PMID:32682163, PMID:34993201]. It additionally restrains vesicle trafficking and fusion—hindering GLUT4 storage vesicle docking by suppressing nonmuscle myosin IIA activity in the SNAP23 complex and modulating AP-3/ESCRT-dependent multivesicular body biogenesis—and is required for skeletal muscle development, sarcomere organization, and focal-adhesion-based mechanosensing [PMID:22809625, PMID:28011197, PMID:25380047, PMID:35929607, PMID:38695862, PMID:39650732].","teleology":[{"year":1991,"claim":"Established the founding member of the septin family as a physical building block of a defined cytoskeletal structure, fixing the question of what septins are.","evidence":"Immunofluorescence of CDC3 fusion-protein antibodies across yeast genetic backgrounds localizing the protein to the mother-bud neck filament ring","pmids":["1993729"],"confidence":"High","gaps":["Did not define the mammalian ortholog's composition or partners","No biochemical filament reconstitution"]},{"year":1999,"claim":"Showed septin ring dynamics are regulated by post-translational modification rather than being static, by demonstrating SUMO (Smt3) conjugation of Cdc3 and its requirement for ring integrity.","evidence":"Immunoprecipitation and immunofluorescence in a ubc9-1 SUMO-conjugation mutant","pmids":["10364461"],"confidence":"Medium","gaps":["SUMO acceptor sites not mapped","Not extended to mammalian SEPT7"]},{"year":2002,"claim":"Identified cell-cycle kinase control of septin ring turnover by placing CDK1/Cdc28 phosphorylation of Cdc3 upstream of G1 ring disassembly.","evidence":"Phospho-site mutagenesis and septin-ring imaging in cln cyclin mutants","pmids":["12429908"],"confidence":"Medium","gaps":["Mammalian relevance of these sites untested","Direct kinase-substrate biochemistry limited"]},{"year":2004,"claim":"Defined the mammalian SEPT7 oligomer by showing it co-purifies and directly binds SEPT2/8/9b/11 and that combinations dictate filament behavior, establishing SEPT7 as a combinatorial assembly hub.","evidence":"Anti-SEPT7 affinity purification, reciprocal co-IP, and co-expression imaging in rat fibroblasts and COS7 cells","pmids":["15485874"],"confidence":"High","gaps":["Stoichiometry/architecture of native complexes not resolved","Functional output of each combination unclear"]},{"year":2007,"claim":"Extended SEPT7 function to neuronal morphogenesis, defining a SEPT5/7/11 complex required for dendritic branching and spine shape.","evidence":"Immunofluorescence, siRNA knockdown, and co-IP in hippocampal neurons","pmids":["17935997"],"confidence":"High","gaps":["Molecular mechanism of spine control not defined at this stage","Upstream regulators unknown"]},{"year":2008,"claim":"Connected SEPT7 to chromosome segregation by showing it directly binds CENP-E and is required for kinetochore CENP-E localization and checkpoint satisfaction.","evidence":"GST pull-down, yeast two-hybrid, siRNA depletion with GFP-SEPT7 rescue in HeLa/MDCK cells","pmids":["18460473"],"confidence":"High","gaps":["Binding interface not mapped","Whether monomeric SEPT7 or filaments engage CENP-E unclear"]},{"year":2012,"claim":"Revealed SEPT7 as a brake on vesicle trafficking, hindering GLUT4 storage vesicle delivery in podocytes via complexes with CD2AP/nephrin and VAMP2.","evidence":"Co-IP, siRNA and forchlorfenuron disruption, glucose uptake assays in podocytes","pmids":["22809625"],"confidence":"High","gaps":["Direct vs scaffold role in vesicle docking not separated","Did not yet identify the myosin effector"]},{"year":2012,"claim":"Implicated SEPT7 in meiotic spindle regulation, showing both loss and excess disrupt microtubule organization and polar body extrusion.","evidence":"Immunofluorescence with siRNA knockdown and mRNA overexpression in mouse oocytes","pmids":["22895176"],"confidence":"Medium","gaps":["Molecular target on the meiotic spindle unidentified","Single-system, single-lab"]},{"year":2013,"claim":"Showed SEPT7 participates in host-pathogen endocytosis through an actin-dependent N-cadherin complex recruited by C. albicans invasins.","evidence":"Affinity purification, siRNA, and cytochalasin D treatment with endocytosis readout in endothelial cells","pmids":["24345743"],"confidence":"Medium","gaps":["Direct SEPT7-N-cadherin contact vs actin-mediated bridging unresolved","Generality beyond Candida unknown"]},{"year":2014,"claim":"Defined the mechanism of SEPT7's essential cytokinetic role as microtubule destabilization, with stathmin acting as the rescuing depolymerizer.","evidence":"Conditional SEPT7 knockout fibroblasts, live imaging, and stathmin supplementation rescue","pmids":["25122120"],"confidence":"High","gaps":["How septins recruit/regulate stathmin not defined","Link to tubulin acetylation machinery unclear"]},{"year":2014,"claim":"Placed SEPT7 (with SEPT6) in endosomal cargo sorting by linking F-actin-bound septins to AP-3 and ESCRT-I membrane interactions.","evidence":"Co-IP, siRNA, and fluorescence microscopy of endosomal dynamics","pmids":["25380047"],"confidence":"Medium","gaps":["Direct adapter contacts not mapped","Role of LRSAM1 ligase mechanistically thin"]},{"year":2016,"claim":"Established SEPT7 as a negative regulator ('molecular brake') of Orai-mediated Ca²⁺ entry with in vivo neural consequences.","evidence":"Bidirectional genetic manipulation in Drosophila neurons with Ca²⁺ imaging and flight assays","pmids":["27225060"],"confidence":"High","gaps":["Domain responsible not yet localized in this study","Direct channel contact vs membrane organization unresolved"]},{"year":2016,"claim":"Identified the trafficking effector for the GLUT4 brake, showing SEPT7 suppresses NM-IIA (MYH9) activity within the SNAP23 complex.","evidence":"Co-IP, siRNA, myosin light-chain phosphorylation Western blots, glucose uptake in podocytes","pmids":["28011197"],"confidence":"Medium","gaps":["How insulin lowers SEPT7 levels not defined","Direct vs indirect myosin inhibition unclear"]},{"year":2016,"claim":"Dissociated SEPT7's cytokinetic function from canonical GTPase-domain filament assembly, showing dimerization-defective mutants still rescue multinucleation.","evidence":"Doxycycline-inducible mutant rescue in SEPT7-null fibroblasts with biochemical GTPase characterization","pmids":["26818767"],"confidence":"Medium","gaps":["What filament state is required remains unknown","Other domains' contribution untested"]},{"year":2017,"claim":"Defined the signaling input for spine maturation by identifying TAOK2 phosphorylation of a conserved SEPT7 C-terminal residue driving spine-head translocation and PSD95 stabilization.","evidence":"Chemical-genetic kinase labeling, mass spectrometry, phospho-mutagenesis, and imaging in neurons","pmids":["28065648"],"confidence":"High","gaps":["How phosphorylation alters septin assembly mechanistically unclear","PSD95-binding interface not mapped"]},{"year":2018,"claim":"Uncovered an unexpected nuclear/transcriptional role, showing SEPT7 binds the CALB2 promoter and represses calretinin in mesothelioma.","evidence":"DNA-binding, ChIP, dual-luciferase, co-IP, and imaging in malignant mesothelioma cells","pmids":["29699512"],"confidence":"Medium","gaps":["Direct vs cofactor-mediated DNA binding unresolved","Generality beyond mesothelioma unknown"]},{"year":2020,"claim":"Defined SEPT7's role in maintaining neural progenitor proliferation via KIF20A retention at the midbody, distinct from a frank cytokinesis defect.","evidence":"Co-IP, siRNA, and inducible NPC-specific Sept7 knockout with cortical phenotyping","pmids":["31813992"],"confidence":"High","gaps":["Mechanism linking KIF20A displacement to differentiation unclear","Direct binding interface not mapped"]},{"year":2020,"claim":"Localized the Ca²⁺-braking activity to the N-terminal polybasic membrane-binding region and linked it to preventing premature STIM1-Orai1 assembly.","evidence":"siRNA, domain-deletion, and TIRF/confocal imaging of Orai1/STIM1 in human neural progenitors","pmids":["32682163"],"confidence":"Medium","gaps":["Direct lipid/channel binding not biochemically reconstituted","How heteromers organize membrane phospholipids unclear"]},{"year":2020,"claim":"Positioned SEPT7 upstream of p150glued in centrosomal microtubule nucleation by showing SEPT7 maintains p150glued abundance.","evidence":"siRNA, co-IP, p150glued-overexpression rescue, and zebrafish embryo experiments","pmids":["32869310"],"confidence":"Medium","gaps":["Mechanism by which SEPT7 stabilizes p150glued unknown","Direct vs indirect interaction unresolved"]},{"year":2021,"claim":"Identified PKA phosphorylation of SEPT7 at Thr197 as a switch disrupting SEPT7-SEPT7 interaction and primary cilium formation.","evidence":"Phospho-mutagenesis, co-IP, cAMP/PKA overexpression, and ciliogenesis imaging","pmids":["33572403"],"confidence":"Medium","gaps":["Structural basis of selective SEPT7-SEPT7 disruption unclear","Cilia phenotype generality untested"]},{"year":2021,"claim":"Placed SEPT7 genetically downstream of STIM1 Ca²⁺ signaling in cerebellar circuit function via epistasis rescue of STIM1-knockout deficits.","evidence":"STIM1 and SEPT7 conditional knockout mice with gene expression, synapse morphology, and rotarod testing","pmids":["34993201"],"confidence":"Medium","gaps":["Molecular link between STIM1 signaling and SEPT7 unclear","Cell-autonomy of the effect not fully resolved"]},{"year":2022,"claim":"Showed 14-3-3 gamma binds TAOK2-phosphorylated SEPT7 (T426) to protect it from dephosphorylation, completing a regulatory loop for spine maturation.","evidence":"Phosphopeptide pulldown, co-IP, imaging, and 14-3-3 antagonist expression in neurons","pmids":["35601601"],"confidence":"Medium","gaps":["Phosphatase counteracting T426 not identified","Structural basis of protection unclear"]},{"year":2022,"claim":"Established SEPT7 as essential for skeletal muscle development, force generation, mitochondrial network organization, and regeneration.","evidence":"Conditional knockdown/knockout mice and C2C12 knockout with force, imaging, and differentiation assays","pmids":["35929607"],"confidence":"High","gaps":["Molecular targets in mitochondrial/sarcomere organization not defined","Whether effects are cytokinesis-dependent unclear"]},{"year":2022,"claim":"Demonstrated cell-type-specific consequences of SEPT7 loss—cytokinesis defect in macrophages without functional impairment, and strong suppression of Kras-driven lung tumorigenesis.","evidence":"Lyz2-Cre and AT2-targeted SEPT7 knockout with phagocytosis, TNF, histopathology, and survival analysis","pmids":["35071236"],"confidence":"Medium","gaps":["Mechanism of tumor suppression undefined","Whether tumor effect is proliferation-dependent unclear"]},{"year":2024,"claim":"Linked SEPT7 to sarcomere structural organization through a Numb interaction required for proper SEPT7 patterning in myofibers.","evidence":"Co-IP proteomics, immunofluorescence, and conditional Numb knockout mice","pmids":["38695862"],"confidence":"Medium","gaps":["Direct binding interface unmapped","Whether Numb organizes or merely co-localizes with SEPT7 unclear"]},{"year":2024,"claim":"Defined integrin/ECM-controlled SEPT7 architectures at focal adhesions required for adhesion elongation, stabilization, and fibroblast mechanosensitivity.","evidence":"TIRF microscopy with siRNA and integrin-activation manipulation in fibroblasts","pmids":["39650732"],"confidence":"Medium","gaps":["Molecular link between integrin activation and SEPT7 assembly unknown","Direct adhesion-complex partners not identified"]},{"year":2024,"claim":"Demonstrated that acute SEPT7 inhibition enhances immune cell motility and tumor infiltration, providing a causal handle on its restraining role in cell deformability.","evidence":"Optogenetic SEPT7-LOV2 inhibition with transmigration and spheroid infiltration assays in NK92 and CD8+ T cells","pmids":["39441641"],"confidence":"Medium","gaps":["Molecular mechanism limiting protrusion not defined","Effect of chronic vs acute inhibition differs and unresolved"]},{"year":null,"claim":"How SEPT7's many context-specific functions—cytokinesis, kinetochore/CENP-E binding, Ca²⁺ channel braking, vesicle trafficking, transcriptional repression, and neuronal scaffolding—are encoded by distinct filament states, partners, and phosphorylation marks remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified structural model linking nucleotide/assembly state to function","Direct binding interfaces for most partners unmapped","How upstream signals select among competing SEPT7 activities is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,15]},{"term_id":"GO:0003924","term_label":"GTPase 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ring of 10-nm filaments at the mother-bud neck in S. cerevisiae, as shown by immunofluorescence with antibodies generated against CDC3 fusion proteins. CDC3 protein assembles into a ring at the budding site before bud emergence and remains organized there after cytokinesis, establishing it as a structural constituent of septin filaments.\",\n      \"method\": \"Immunofluorescence with polyclonal antibodies raised against CDC3 fusion proteins in wild-type and mutant yeast cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence, replicated across multiple genetic backgrounds and time points, consistent with prior CDC12 data\",\n      \"pmids\": [\"1993729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The yeast SUMO-1 homolog Smt3 is conjugated to Cdc3 (yeast SEPT7 ortholog) at the mother-bud neck septin rings, as demonstrated by immunoprecipitation. Loss of Smt3 conjugation (in a ubc9-1 mutant) results in disappearance of septin rings and reduction of the Cdc3-Smt3 conjugate. The conjugate disappears around the time of cytokinesis, indicating SUMO modification of Cdc3 regulates septin ring dynamics.\",\n      \"method\": \"Immunoprecipitation, indirect immunofluorescence, genetic analysis using ubc9-1 mutant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP plus localization with functional consequence in a defined mutant background, single lab\",\n      \"pmids\": [\"10364461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The yeast septin Cdc3 is phosphorylated near its C-terminus by the Cdc28 (CDK1) kinase in a cell-cycle-dependent manner. Mutation of the Cdc28-dependent phosphorylation sites impairs disassembly of the old septin ring inherited at mitosis; G1 cyclin function is required for efficient ring disassembly, placing CDK-mediated Cdc3 phosphorylation as a regulator of septin ring turnover at G1.\",\n      \"method\": \"Phospho-site mutagenesis, immunofluorescence analysis of septin ring dynamics in wild-type and cln mutants\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of phosphorylation sites plus cell-cycle genetic analysis, single lab\",\n      \"pmids\": [\"12429908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mammalian SEPT7 is a component of a septin complex with SEPT9b and SEPT11 in rat fibroblasts. Affinity purification with anti-SEPT7 antibody co-purified SEPT2, SEPT7, SEPT8, SEPT9b, and SEPT11. SEPT7, SEPT9b, and SEPT11 co-localize along stress fibers and directly bind each other through their N- or C-terminal divergent regions. Co-expression experiments in COS7 cells reveal combination-dependent filament elongation, bundling, or disruption.\",\n      \"method\": \"Anti-SEPT7 antibody affinity purification, immunoprecipitation, immunofluorescence, transient co-expression in COS7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — affinity purification plus reciprocal immunoprecipitation plus cell imaging, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15485874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SEPT7 localizes to the bases of filopodia and dendritic branch points in developing hippocampal neurons and to the bases of dendritic spines in mature neurons. Downregulation of SEPT7 impairs dendritic branching and causes elongated spine morphology. SEPT5 and SEPT11 co-localize with and co-immunoprecipitate with SEPT7, indicating existence of a SEPT5/7/11 complex in neurons.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown, co-immunoprecipitation in hippocampal neurons\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, direct localization experiments with functional consequences (knockdown phenotype), multiple orthogonal methods\",\n      \"pmids\": [\"17935997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SEPT7 directly interacts with the C-terminal domain of the kinetochore motor CENP-E, as demonstrated by GST pull-down and yeast two-hybrid assays. SEPT7 filaments distribute along the mitotic spindle and terminate at the kinetochore. siRNA-mediated depletion of SEPT7 abolishes kinetochore localization of CENP-E, reduces kinetochore tension, activates the spindle checkpoint (Mad2, BubR1), and causes chromosome mis-segregation; all phenotypes are rescued by exogenous GFP-SEPT7.\",\n      \"method\": \"GST pull-down, yeast two-hybrid, immunofluorescence, siRNA knockdown with rescue experiment in HeLa and MDCK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro pull-down plus yeast two-hybrid plus cell-based siRNA with defined phenotype and rescue, multiple orthogonal methods\",\n      \"pmids\": [\"18460473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SEPT7 forms a complex with CD2AP and nephrin in podocytes and co-immunoprecipitates with VAMP2. Filamentous localization of SEPT7 depends on CD2AP and intact actin organization. siRNA-mediated depletion of SEPT7 or pharmacological disruption of septin assembly with forchlorfenuron facilitates glucose uptake into podocytes and increases VAMP2 interaction with nephrin and syntaxin 4, indicating SEPT7 hinders GLUT4 storage vesicle (GSV) trafficking.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, immunofluorescence, 2-deoxy-D-glucose uptake assay in cultured podocytes\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus functional uptake assay plus localization with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"22809625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SEPT7 localizes to the meiotic spindle from pro-MI to MII stages in mouse oocytes. Knockdown of SEPT7 causes abnormal spindles and impairs extrusion of the first polar body. Overexpressed Myc-SEPT7 localizes to spindles and plasma membrane; overexpression weakens spindle α-tubulin fluorescence intensity and disrupts chromosome alignment and polar body extrusion, indicating SEPT7 regulates microtubule dynamics during meiosis.\",\n      \"method\": \"Immunofluorescence, siRNA microinjection knockdown, mRNA overexpression in mouse oocytes\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization plus loss- and gain-of-function with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"22895176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Genetic deletion of SEPT7 in mouse fibroblasts causes multinucleation due to failure of cytokinesis, associated with hyperacetylation/stabilization of microtubules and stalled midbody abscission. Supplementation with the microtubule-depolymerizing protein stathmin rescues cytokinesis failure in SEPT7-null fibroblasts. Knockdown of stathmin sensitizes a hematopoietic cell line to the septin inhibitor forchlorfenuron, establishing that septin-dependent cytokinesis requires microtubule destabilization via stathmin.\",\n      \"method\": \"Conditional genetic knockout (SEPT7-floxed mice), live-cell imaging, stathmin supplementation rescue, siRNA knockdown, forchlorfenuron treatment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined phenotype, mechanistic rescue by stathmin, multiple cell types and orthogonal approaches\",\n      \"pmids\": [\"25122120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SEPT6 and SEPT7 complexes bound to F-actin regulate multivesicular body (MVB) biogenesis by binding AP-3 (an endosomal adapter complex), modulating AP-3 membrane interactions and motility of AP-3-positive endosomes, and influencing ESCRT-I membrane interaction during cargo sorting. This coordination requires the E3 ubiquitin ligase LRSAM1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy of endosomal dynamics\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus cell-based functional readout, single lab with multiple methods\",\n      \"pmids\": [\"25380047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SEPT7 acts as a negative regulator ('molecular brake') of Orai channel-mediated Ca²⁺ entry in Drosophila neurons. Lowering SEPT7 levels results in store-independent dOrai-mediated Ca²⁺ entry and elevated cytosolic Ca²⁺ at rest. Overexpression of SEPT7 reduces both store-operated Ca²⁺ entry (SOCE) and flight duration in vivo, demonstrating that SEPT7 modulates Orai channel function and neural circuit activity.\",\n      \"method\": \"Genetic knockdown and overexpression in Drosophila neurons, Ca²⁺ imaging, in vivo flight assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (KD and OE) with in vivo and in vitro functional readouts, replicated across multiple assays\",\n      \"pmids\": [\"27225060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SEPT7 forms a complex with nonmuscle myosin heavy chain IIA (NMHC-IIA/MYH9) and SNAP23. Insulin decreases SEPT7 levels and increases NM-IIA activity in the SNAP23 complex. Knockdown of SEPT7 increases NM-IIA activity (measured by myosin regulatory light chain phosphorylation) in the SNAP23 complex and thereby facilitates GLUT4 storage vesicle docking and fusion with the plasma membrane, indicating SEPT7 hinders GSV fusion by suppressing NM-IIA activity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Western blot for myosin light chain phosphorylation, glucose uptake assay in podocytes\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional assay with defined molecular mechanism, single lab\",\n      \"pmids\": [\"28011197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GTPase domain-driven dimerization of SEPT7 is dispensable for its essential role in fibroblast cytokinesis. SEPT7 mutants with altered GTPase domain-dependent homo- or hetero-polymerization, GTP-binding, or GTPase activity can still rescue multinucleation in Sept7-null fibroblasts, indicating that well-defined native filament assembly via GTPase domain dimerization is not required for SEPT7's cytokinetic function.\",\n      \"method\": \"Conditional genetic knockout fibroblast system with doxycycline-inducible SEPT7 mutant rescue, biochemical analysis of GTPase mutants\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genetic rescue system with biochemically characterized mutants, single lab\",\n      \"pmids\": [\"26818767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The kinase TAOK2 directly phosphorylates SEPT7 at an evolutionarily conserved C-terminal residue (identified by chemical-genetics and mass spectrometry). This phosphorylation induces translocation of SEPT7 into the dendritic spine head, where SEPT7 associates with and stabilizes the scaffolding protein PSD95, promoting dendritic spine maturation and compartmentalization of NMDA receptor-mediated calcium influx.\",\n      \"method\": \"Chemical-genetic kinase labeling, mass spectrometry, phospho-site mutagenesis, live-cell imaging, co-immunoprecipitation in neurons\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — chemical-genetics plus MS identification plus mutagenesis plus functional rescue, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"28065648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEPT7 binds to the CALB2 (calretinin) gene promoter in a butyrate-dependent manner and acts as a transcriptional repressor of calretinin expression in malignant mesothelioma cells. Overexpression of SEPT7 decreases calretinin levels; conversely, calretinin overexpression decreases SEPT7 levels. SEPT7 and calretinin directly interact, as shown by co-immunoprecipitation, and co-localize in the cleavage furrow and midbody during cytokinesis.\",\n      \"method\": \"DNA-binding assays, peptide shotgun-mass spectrometry, dual-luciferase reporter assays, chromatin immunoprecipitation, lentiviral overexpression/knockdown, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (DNA binding, reporter assay, co-IP, imaging), single lab\",\n      \"pmids\": [\"29699512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"High-resolution crystal structures of the SEPT7 GTPase domain complexed with GDP reveal coordination details of the magnesium ion and the molecular basis for interactions at the G-interface. A structural motif based on an antiparallel β-bridge at the G-interface rationalizes why SEPT7 (unlike some other septins) does not undergo nucleotide-dependent β-strand slippage, providing insight into filament assembly mechanisms.\",\n      \"method\": \"X-ray crystallography (two high-resolution structures of SEPT7 GTPase domain-GDP complex)\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structures with structural analysis, single lab but rigorous method\",\n      \"pmids\": [\"31009756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEPT7 interacts with KIF20A in the intercellular bridge of dividing neural progenitor cells (NPCs). Knockdown of SEPT7 displaces KIF20A from the midbody and triggers precocious neuronal differentiation. NPC-specific inducible knockout of Sept7 causes early cell cycle exit, precocious neuronal differentiation, and ventriculomegaly without a noticeable cytokinesis defect, indicating SEPT7 maintains the proliferative state of NPCs through KIF20A-mediated mechanisms.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, conditional inducible knockout mouse model, cortical phenotype analysis\",\n      \"journal\": \"Cerebral cortex (New York, N.Y. : 1991)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP establishing interaction, in vivo knockout with defined phenotype, knockdown with mechanistic displacement of KIF20A, multiple orthogonal approaches\",\n      \"pmids\": [\"31813992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEPT7 prevents constitutive Ca²⁺ entry through Orai channels in human neural progenitor cells (hNPCs) and differentiated neurons. The N-terminal polybasic region of SEPT7, known to interact with membrane phospholipids, is essential for this inhibitory function (whereas the GTPase domain of dSEPT7 is dispensable). SEPT7 knockdown causes reorganization of Orai1 and STIM1 near the plasma membrane, supporting a model where SEPT7-containing heteromers prevent premature STIM-Orai complex activation.\",\n      \"method\": \"siRNA knockdown, Ca²⁺ imaging, domain-deletion analysis, TIRF/confocal microscopy of Orai1 and STIM1 localization in hNPCs\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion experiments plus imaging with functional Ca²⁺ readout, single lab\",\n      \"pmids\": [\"32682163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEPT7 localizes to the centrosome, and depletion of SEPT7 causes aberrant mitotic spindle pole formation and disorganized microtubule nucleation. SEPT7 forms a complex with p150glued (a centriole subdistal appendage component), and SEPT7 depletion reduces the abundance of p150glued. Overexpression of p150glued reverses the microtubule nucleation defects caused by SEPT7 deficiency, placing SEPT7 upstream of p150glued in microtubule array organization.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, immunofluorescence, rescue by p150glued overexpression, zebrafish embryo experiments\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional rescue establishes pathway position, single lab with multiple methods\",\n      \"pmids\": [\"32869310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Protein kinase A (PKA) phosphorylates SEPT7 at Thr197, disrupting septin filament dynamics and primary cilia formation. Treatment with cAMP or overexpression of PKA catalytic subunit induces SEPT7 Thr197 phosphorylation. Constitutive phosphorylation at Thr197 reduces SEPT7-SEPT7 interaction but does not affect SEPT7-SEPT6-SEPT2 or SEPT4 interaction. SEPT7 interacts with PKACA2 via its GTP-binding domain.\",\n      \"method\": \"Phospho-site mutagenesis, co-immunoprecipitation, cAMP/PKA overexpression, immunofluorescence of septin filaments and primary cilia\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis plus co-IP plus functional ciliogenesis readout, single lab\",\n      \"pmids\": [\"33572403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of SEPT7 in Purkinje neurons rescues motor coordination deficits and aberrant climbing fiber innervation caused by STIM1 knockout. Loss of SEPT7 (one or two copies) in STIM1-knockout Purkinje neurons restores expression of a subset of genes including neuron projection development genes and normalizes CF-PN innervation, establishing that SEPT7 acts downstream of STIM1-dependent Ca²⁺ signaling in cerebellar circuit function.\",\n      \"method\": \"Conditional knockout mouse models (STIM1 and SEPT7), gene expression analysis, synapse morphology, rotarod behavioral testing\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo with behavioral and molecular readouts, single lab\",\n      \"pmids\": [\"34993201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"14-3-3 proteins (specifically 14-3-3 gamma) interact with SEPT7 in a phosphorylation-dependent manner, specifically when SEPT7 is phosphorylated at T426 (the TAOK2 phosphorylation site). 14-3-3 gamma is enriched in mature dendritic spine heads. Expression of a 14-3-3 antagonist significantly decreases phospho-SEPT7 levels in neurons, indicating that 14-3-3 binding protects phosphorylated SEPT7 from dephosphorylation.\",\n      \"method\": \"Phosphopeptide pulldown, co-immunoprecipitation, immunofluorescence in neurons, 14-3-3 antagonist expression\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphopeptide pulldown plus co-IP plus functional antagonist experiment, single lab with two orthogonal methods\",\n      \"pmids\": [\"35601601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional knockdown of Septin7 in mice causes hunchback phenotype with skeletal deformities, reduced in vivo and in vitro muscle force, and disorganized mitochondrial networks. Knockout of Septin7 in C2C12 cells abolishes cell division. Knockdown in C2C12 cells impairs myotube differentiation. Septin7 expression transiently increases following muscle injury, suggesting a role in muscle regeneration and development.\",\n      \"method\": \"Conditional knockout/knockdown mouse model, C2C12 cell knockout, immunofluorescence, force measurement, confocal microscopy\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with multiple defined phenotypic readouts plus cell-based experiments, multiple orthogonal approaches\",\n      \"pmids\": [\"35929607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEPT7 deletion in macrophages (via Lyz2-Cre) causes constitutive double-nucleation indicating a cytokinesis defect, but does not impair phagocytic function or LPS-stimulated TNF production. In AT2 cells, SEPT7 deletion dramatically suppresses oncogenic Kras-G12D-driven lung tumorigenesis, with control mice dying in 3-5 weeks while SEPT7-deficient animals survived 11+ weeks.\",\n      \"method\": \"Conditional genetic knockout (Lyz2-Cre × SEPT7-floxed), phagocytosis assay, TNF ELISA, histopathology, survival analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic deletion with defined cellular phenotypes (cytokinesis defect, tumor suppression), single lab\",\n      \"pmids\": [\"35071236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEPT7 forms a complex with N-cadherin in endothelial cells, and this complex is recruited by C. albicans Als3 and Ssa1 invasins. N-cadherin acts as a link between SEPT7 and the fungus; knockdown of N-cadherin reduces SEPT7 recruitment. SEPT7 knockdown decreases N-cadherin accumulation around C. albicans and significantly inhibits endocytosis of the organism. Intact actin microfilaments are required for SEPT7-N-cadherin association.\",\n      \"method\": \"Confocal microscopy, affinity purification, siRNA knockdown, cytochalasin D actin depolymerization\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification plus siRNA with defined endocytosis readout, single lab with multiple methods\",\n      \"pmids\": [\"24345743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEPT3 directly binds to SEPT5 and SEPT7 and forms a heteromeric complex at nerve terminals in mature neurons. In Sept3-null mice, expression of other septins including SEPT7 is unaltered, and SEPT3 is dispensable for normal neuronal development.\",\n      \"method\": \"Direct binding assay, co-immunoprecipitation, immunofluorescence in primary neurons, Sept3 knockout mouse analysis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus co-IP establishing complex membership, single lab\",\n      \"pmids\": [\"17564677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEPT7 interacts with Numb in C2C12 myotubes (identified by proteomics of Numb immunoprecipitates). Immunofluorescence reveals partial overlap of Numb and SEPT7 in myofibers. Conditional knockout of Numb causes disorganization of SEPT7 staining in myofibers, indicating Numb-SEPT7 interactions are critical for sarcomere structural organization.\",\n      \"method\": \"Co-immunoprecipitation proteomics, immunofluorescence, conditional knockout mouse model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by co-IP and in vivo disorganization phenotype, single lab\",\n      \"pmids\": [\"38695862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ECM-mediated integrin activation regulates spatially distinct SEPT7 structures at focal adhesions (FAs) in fibroblasts. In perinuclear regions, ECM binding stabilizes SEPT7 bundles at the back of FAs; in peripheral FAs, high integrin activation promotes elongation of SEPT7 structures. Ventral SEPT7 structures are required for FA elongation, stabilization, and fibroblast mechanosensitivity.\",\n      \"method\": \"Total internal reflection fluorescence (TIRF) microscopy, siRNA knockdown, integrin activation manipulation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence via TIRF, single lab with defined phenotypic readout\",\n      \"pmids\": [\"39650732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Blue light-induced inhibition of an engineered SEPT7-LOV2 hybrid protein in NK92 cells and CD8+ T cells induces extended cell protrusions and cell polarization, enhancing transmigration through confining spaces and improving penetration into tumor spheroids. This demonstrates that inhibiting SEPT7 function promotes immune cell infiltration by enhancing cell motility.\",\n      \"method\": \"Optogenetic protein engineering, live-cell imaging, transmigration assay, tumor spheroid infiltration assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered optogenetic system with defined functional readout, single study with multiple cell types\",\n      \"pmids\": [\"39441641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEPT7 (via Sept7 variant 4) suppresses Bax-mediated apoptosis in yeast and also confers resistance to copper-mediated cell death in a caspase-independent manner. The yeast SEPT7 ortholog CDC10 similarly protects against copper toxicity and Bax expression. SEPT7 was unable to rescue the cell size increase of cdc10Δ yeast, indicating distinct functions for the anti-apoptotic versus cytoskeletal roles.\",\n      \"method\": \"Heterologous expression screen in yeast, cell viability assay, caspase-deficient (mca1Δ) strain analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast expression system with viability readout, indirect assay for apoptosis suppression, single lab\",\n      \"pmids\": [\"24055994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SEPT2 and SEPT7 depletion in MDA-MB-231 breast cancer cells inhibits migration and invasion, while overexpression enhances these behaviors. MEK/ERK activation is positively correlated with SEPT2 and SEPT7 protein levels, and MEK inhibitor U0126 normalizes increased invasiveness in SEPT7-overexpressing cells, placing SEPT7 upstream of MEK/ERK in regulating cancer cell invasion.\",\n      \"method\": \"siRNA knockdown, forced overexpression, Transwell migration/invasion assays, MEK inhibitor treatment, Western blot for MAPK signaling\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell-based knockdown/overexpression with pathway inhibitor, single lab, correlation-based pathway placement\",\n      \"pmids\": [\"27557506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEPT7 interacts with DOCK8 in primary equine lymphocytes, as identified by interaction proteomics. DOCK8 expression and its interaction network are significantly altered in equine recurrent uveitis (autoimmune disease), and ILK is identified as a DOCK8 interactor in lymphocytes.\",\n      \"method\": \"Interaction proteomics (immunoprecipitation-mass spectrometry), Western blot validation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP/proteomics experiment in primary cells, single lab, no mechanistic follow-up for SEPT7-DOCK8 interaction\",\n      \"pmids\": [\"30120291\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEPT7 is an essential, ubiquitously expressed GTP-binding cytoskeletal protein that serves as the central organizing subunit of all mammalian hetero-oligomeric septin complexes (including SEPT2/6/7/9/11 hexamers and octamers); it localizes to stress fibers, the cleavage furrow and midbody during cytokinesis (where it promotes microtubule destabilization via stathmin), to centrosomes (where it maintains p150glued abundance for microtubule nucleation), to the base of dendritic spines and branch points in neurons (where phosphorylation by TAOK2 at a conserved C-terminal residue drives spine maturation by stabilizing PSD95, an effect protected by 14-3-3 binding), and to focal adhesions in fibroblasts; SEPT7 acts as a negative regulator of Orai channel-mediated Ca²⁺ entry through its N-terminal polybasic phospholipid-binding region, stabilizes kinetochore localization of CENP-E by direct interaction to ensure chromosome segregation, hinders GLUT4 vesicle docking by suppressing nonmuscle myosin IIA activity in the SNAP23 complex, and can also function as a transcriptional repressor at the CALB2 promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEPTIN7 is the central organizing subunit of mammalian hetero-oligomeric septin complexes and functions as a GTP-binding cytoskeletal scaffold that couples membrane and microtubule/actin dynamics to cell division, neuronal architecture, and Ca²⁺ signaling [#3, #15]. From its earliest characterization as the yeast CDC3 ortholog forming the mother-bud neck filament ring, the protein has served as a structural constituent of septin filaments whose assembly and turnover are controlled by post-translational modification, including SUMO conjugation and cell-cycle-dependent CDK phosphorylation [#0, #1, #2]. In mammalian cells SEPT7 assembles into combinatorial filaments with partners such as SEPT2, SEPT9b, and SEPT11 along stress fibers, and its essential role in cytokinesis operates through microtubule destabilization: SEPT7 loss stabilizes/hyperacetylates microtubules and stalls midbody abscission, a defect rescued by the depolymerizing factor stathmin [#3, #8]. This cytokinetic function is genetically separable from GTPase-domain-driven filament dimerization, which is dispensable for rescue of multinucleation [#12]. During mitosis SEPT7 directly binds the kinetochore motor CENP-E to ensure its kinetochore localization, chromosome alignment, and satisfaction of the spindle checkpoint, and organizes centrosomal microtubule nucleation by maintaining p150glued abundance [#5, #18]. In the nervous system, SEPT7 localizes to the bases of dendritic branch points and spines and controls spine maturation: TAOK2 phosphorylates a conserved C-terminal residue (T426) to drive SEPT7 into spine heads where it stabilizes PSD95, an event protected from dephosphorylation by 14-3-3 gamma binding [#4, #13, #21]. SEPT7 acts as a negative regulator of Orai-channel-mediated Ca²⁺ entry through its membrane-phospholipid-binding N-terminal polybasic region, preventing premature STIM-Orai activation, and functions downstream of STIM1 in cerebellar circuit wiring [#10, #17, #20]. It additionally restrains vesicle trafficking and fusion—hindering GLUT4 storage vesicle docking by suppressing nonmuscle myosin IIA activity in the SNAP23 complex and modulating AP-3/ESCRT-dependent multivesicular body biogenesis—and is required for skeletal muscle development, sarcomere organization, and focal-adhesion-based mechanosensing [#6, #11, #9, #22, #26, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established the founding member of the septin family as a physical building block of a defined cytoskeletal structure, fixing the question of what septins are.\",\n      \"evidence\": \"Immunofluorescence of CDC3 fusion-protein antibodies across yeast genetic backgrounds localizing the protein to the mother-bud neck filament ring\",\n      \"pmids\": [\"1993729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the mammalian ortholog's composition or partners\", \"No biochemical filament reconstitution\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed septin ring dynamics are regulated by post-translational modification rather than being static, by demonstrating SUMO (Smt3) conjugation of Cdc3 and its requirement for ring integrity.\",\n      \"evidence\": \"Immunoprecipitation and immunofluorescence in a ubc9-1 SUMO-conjugation mutant\",\n      \"pmids\": [\"10364461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO acceptor sites not mapped\", \"Not extended to mammalian SEPT7\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified cell-cycle kinase control of septin ring turnover by placing CDK1/Cdc28 phosphorylation of Cdc3 upstream of G1 ring disassembly.\",\n      \"evidence\": \"Phospho-site mutagenesis and septin-ring imaging in cln cyclin mutants\",\n      \"pmids\": [\"12429908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian relevance of these sites untested\", \"Direct kinase-substrate biochemistry limited\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the mammalian SEPT7 oligomer by showing it co-purifies and directly binds SEPT2/8/9b/11 and that combinations dictate filament behavior, establishing SEPT7 as a combinatorial assembly hub.\",\n      \"evidence\": \"Anti-SEPT7 affinity purification, reciprocal co-IP, and co-expression imaging in rat fibroblasts and COS7 cells\",\n      \"pmids\": [\"15485874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/architecture of native complexes not resolved\", \"Functional output of each combination unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended SEPT7 function to neuronal morphogenesis, defining a SEPT5/7/11 complex required for dendritic branching and spine shape.\",\n      \"evidence\": \"Immunofluorescence, siRNA knockdown, and co-IP in hippocampal neurons\",\n      \"pmids\": [\"17935997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of spine control not defined at this stage\", \"Upstream regulators unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected SEPT7 to chromosome segregation by showing it directly binds CENP-E and is required for kinetochore CENP-E localization and checkpoint satisfaction.\",\n      \"evidence\": \"GST pull-down, yeast two-hybrid, siRNA depletion with GFP-SEPT7 rescue in HeLa/MDCK cells\",\n      \"pmids\": [\"18460473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface not mapped\", \"Whether monomeric SEPT7 or filaments engage CENP-E unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed SEPT7 as a brake on vesicle trafficking, hindering GLUT4 storage vesicle delivery in podocytes via complexes with CD2AP/nephrin and VAMP2.\",\n      \"evidence\": \"Co-IP, siRNA and forchlorfenuron disruption, glucose uptake assays in podocytes\",\n      \"pmids\": [\"22809625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs scaffold role in vesicle docking not separated\", \"Did not yet identify the myosin effector\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Implicated SEPT7 in meiotic spindle regulation, showing both loss and excess disrupt microtubule organization and polar body extrusion.\",\n      \"evidence\": \"Immunofluorescence with siRNA knockdown and mRNA overexpression in mouse oocytes\",\n      \"pmids\": [\"22895176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target on the meiotic spindle unidentified\", \"Single-system, single-lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed SEPT7 participates in host-pathogen endocytosis through an actin-dependent N-cadherin complex recruited by C. albicans invasins.\",\n      \"evidence\": \"Affinity purification, siRNA, and cytochalasin D treatment with endocytosis readout in endothelial cells\",\n      \"pmids\": [\"24345743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SEPT7-N-cadherin contact vs actin-mediated bridging unresolved\", \"Generality beyond Candida unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the mechanism of SEPT7's essential cytokinetic role as microtubule destabilization, with stathmin acting as the rescuing depolymerizer.\",\n      \"evidence\": \"Conditional SEPT7 knockout fibroblasts, live imaging, and stathmin supplementation rescue\",\n      \"pmids\": [\"25122120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How septins recruit/regulate stathmin not defined\", \"Link to tubulin acetylation machinery unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SEPT7 (with SEPT6) in endosomal cargo sorting by linking F-actin-bound septins to AP-3 and ESCRT-I membrane interactions.\",\n      \"evidence\": \"Co-IP, siRNA, and fluorescence microscopy of endosomal dynamics\",\n      \"pmids\": [\"25380047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct adapter contacts not mapped\", \"Role of LRSAM1 ligase mechanistically thin\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SEPT7 as a negative regulator ('molecular brake') of Orai-mediated Ca²⁺ entry with in vivo neural consequences.\",\n      \"evidence\": \"Bidirectional genetic manipulation in Drosophila neurons with Ca²⁺ imaging and flight assays\",\n      \"pmids\": [\"27225060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain responsible not yet localized in this study\", \"Direct channel contact vs membrane organization unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the trafficking effector for the GLUT4 brake, showing SEPT7 suppresses NM-IIA (MYH9) activity within the SNAP23 complex.\",\n      \"evidence\": \"Co-IP, siRNA, myosin light-chain phosphorylation Western blots, glucose uptake in podocytes\",\n      \"pmids\": [\"28011197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How insulin lowers SEPT7 levels not defined\", \"Direct vs indirect myosin inhibition unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissociated SEPT7's cytokinetic function from canonical GTPase-domain filament assembly, showing dimerization-defective mutants still rescue multinucleation.\",\n      \"evidence\": \"Doxycycline-inducible mutant rescue in SEPT7-null fibroblasts with biochemical GTPase characterization\",\n      \"pmids\": [\"26818767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What filament state is required remains unknown\", \"Other domains' contribution untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the signaling input for spine maturation by identifying TAOK2 phosphorylation of a conserved SEPT7 C-terminal residue driving spine-head translocation and PSD95 stabilization.\",\n      \"evidence\": \"Chemical-genetic kinase labeling, mass spectrometry, phospho-mutagenesis, and imaging in neurons\",\n      \"pmids\": [\"28065648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters septin assembly mechanistically unclear\", \"PSD95-binding interface not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered an unexpected nuclear/transcriptional role, showing SEPT7 binds the CALB2 promoter and represses calretinin in mesothelioma.\",\n      \"evidence\": \"DNA-binding, ChIP, dual-luciferase, co-IP, and imaging in malignant mesothelioma cells\",\n      \"pmids\": [\"29699512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs cofactor-mediated DNA binding unresolved\", \"Generality beyond mesothelioma unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined SEPT7's role in maintaining neural progenitor proliferation via KIF20A retention at the midbody, distinct from a frank cytokinesis defect.\",\n      \"evidence\": \"Co-IP, siRNA, and inducible NPC-specific Sept7 knockout with cortical phenotyping\",\n      \"pmids\": [\"31813992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking KIF20A displacement to differentiation unclear\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Localized the Ca²⁺-braking activity to the N-terminal polybasic membrane-binding region and linked it to preventing premature STIM1-Orai1 assembly.\",\n      \"evidence\": \"siRNA, domain-deletion, and TIRF/confocal imaging of Orai1/STIM1 in human neural progenitors\",\n      \"pmids\": [\"32682163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lipid/channel binding not biochemically reconstituted\", \"How heteromers organize membrane phospholipids unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned SEPT7 upstream of p150glued in centrosomal microtubule nucleation by showing SEPT7 maintains p150glued abundance.\",\n      \"evidence\": \"siRNA, co-IP, p150glued-overexpression rescue, and zebrafish embryo experiments\",\n      \"pmids\": [\"32869310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SEPT7 stabilizes p150glued unknown\", \"Direct vs indirect interaction unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified PKA phosphorylation of SEPT7 at Thr197 as a switch disrupting SEPT7-SEPT7 interaction and primary cilium formation.\",\n      \"evidence\": \"Phospho-mutagenesis, co-IP, cAMP/PKA overexpression, and ciliogenesis imaging\",\n      \"pmids\": [\"33572403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of selective SEPT7-SEPT7 disruption unclear\", \"Cilia phenotype generality untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SEPT7 genetically downstream of STIM1 Ca²⁺ signaling in cerebellar circuit function via epistasis rescue of STIM1-knockout deficits.\",\n      \"evidence\": \"STIM1 and SEPT7 conditional knockout mice with gene expression, synapse morphology, and rotarod testing\",\n      \"pmids\": [\"34993201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between STIM1 signaling and SEPT7 unclear\", \"Cell-autonomy of the effect not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed 14-3-3 gamma binds TAOK2-phosphorylated SEPT7 (T426) to protect it from dephosphorylation, completing a regulatory loop for spine maturation.\",\n      \"evidence\": \"Phosphopeptide pulldown, co-IP, imaging, and 14-3-3 antagonist expression in neurons\",\n      \"pmids\": [\"35601601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphatase counteracting T426 not identified\", \"Structural basis of protection unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established SEPT7 as essential for skeletal muscle development, force generation, mitochondrial network organization, and regeneration.\",\n      \"evidence\": \"Conditional knockdown/knockout mice and C2C12 knockout with force, imaging, and differentiation assays\",\n      \"pmids\": [\"35929607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets in mitochondrial/sarcomere organization not defined\", \"Whether effects are cytokinesis-dependent unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated cell-type-specific consequences of SEPT7 loss—cytokinesis defect in macrophages without functional impairment, and strong suppression of Kras-driven lung tumorigenesis.\",\n      \"evidence\": \"Lyz2-Cre and AT2-targeted SEPT7 knockout with phagocytosis, TNF, histopathology, and survival analysis\",\n      \"pmids\": [\"35071236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of tumor suppression undefined\", \"Whether tumor effect is proliferation-dependent unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SEPT7 to sarcomere structural organization through a Numb interaction required for proper SEPT7 patterning in myofibers.\",\n      \"evidence\": \"Co-IP proteomics, immunofluorescence, and conditional Numb knockout mice\",\n      \"pmids\": [\"38695862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface unmapped\", \"Whether Numb organizes or merely co-localizes with SEPT7 unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined integrin/ECM-controlled SEPT7 architectures at focal adhesions required for adhesion elongation, stabilization, and fibroblast mechanosensitivity.\",\n      \"evidence\": \"TIRF microscopy with siRNA and integrin-activation manipulation in fibroblasts\",\n      \"pmids\": [\"39650732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between integrin activation and SEPT7 assembly unknown\", \"Direct adhesion-complex partners not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that acute SEPT7 inhibition enhances immune cell motility and tumor infiltration, providing a causal handle on its restraining role in cell deformability.\",\n      \"evidence\": \"Optogenetic SEPT7-LOV2 inhibition with transmigration and spheroid infiltration assays in NK92 and CD8+ T cells\",\n      \"pmids\": [\"39441641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism limiting protrusion not defined\", \"Effect of chronic vs acute inhibition differs and unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEPT7's many context-specific functions—cytokinesis, kinetochore/CENP-E binding, Ca²⁺ channel braking, vesicle trafficking, transcriptional repression, and neuronal scaffolding—are encoded by distinct filament states, partners, and phosphorylation marks remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model linking nucleotide/assembly state to function\", \"Direct binding interfaces for most partners unmapped\", \"How upstream signals select among competing SEPT7 activities is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 15]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [12, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 8, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 27]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 17]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 8, 16, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 17, 20]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 9, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 13, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 22]}\n    ],\n    \"complexes\": [\n      \"SEPT2/7/9b/11 hetero-oligomeric septin complex\",\n      \"SEPT5/7/11 neuronal septin complex\",\n      \"SNAP23-NMHC-IIA complex\",\n      \"CD2AP-nephrin complex\"\n    ],\n    \"partners\": [\n      \"CENP-E\",\n      \"TAOK2\",\n      \"PSD95\",\n      \"KIF20A\",\n      \"MYH9\",\n      \"p150glued\",\n      \"Numb\",\n      \"SEPT11\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"SEPTIN7","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 35601601"},"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}