SEPTIN10

SEPTIN10 is a GTP-binding, GTPase-active member of the septin cytoskeletal family that assembles into heteromeric septin complexes and regulates the interplay between the actin and microtubule cytoskeletons (PMID:12711328, PMID:23087102, PMID:38242197). It binds and hydrolyzes GTP and localizes to both cytoplasm and nucleus independently of the filamentous actin state (PMID:12711328). In cells it partitions into distinct higher-order septin assemblies—co-precipitating with SEPT7, SEPT8, SEPT9, SEPT11, and SEPT14 along microtubules in carcinoma cells (PMID:23087102), and with SEPT1, SEPT2, SEPT11, and SEPT12 at the sperm neck where it supports connecting-piece assembly (PMID:32392324). Mechanistically, SEPTIN10 functions as a molecular switch coupling the two cytoskeletons: it binds CAPZA2 to promote actin stress fiber formation and intracellular tension while blocking MAP4 to inhibit microtubule polymerization, with loss of SEPTIN10 abrogating actin stress fiber formation after microtubule disruption and feeding back to activate YAP/TAZ mechanosignaling in hepatocellular carcinoma cells (PMID:38242197). Consistent with a role in microtubule stability, SEPTIN10 levels set sensitivity to the microtubule-targeting agent paclitaxel (PMID:22320903), and the protein is required to maintain the podocyte cytoskeleton (PMID:28709640). In the male germline, SEPTIN10 physically interacts with androglobin, which directs its localization at the manchette and sperm annulus and contributes to its calmodulin-dependent proteolysis (PMID:35700329).

1. 2003 Medium

   Establishing whether SEPTIN10 is a functional GTPase defined its core biochemical identity as a nucleotide-binding septin and showed its localization is uncoupled from the actin cytoskeleton.

   Evidence In vitro GTP-binding/GTPase assay and GFP-fusion live-cell imaging

   PMID:12711328

   Open questions at the time

   • No mutagenesis of the GTP-binding motif to link catalysis to function
   • No structural model of nucleotide binding
   • Subcellular targeting determinants unresolved
2. 2012 Medium

   A functional genomics screen connected SEPTIN10 dosage to microtubule stability and chemosensitivity, showing it regulates a drug-relevant cytoskeletal phenotype.

   Evidence Lentiviral siRNA screen with siRNA knockdown and overexpression assays scoring paclitaxel sensitivity

   PMID:22320903

   Open questions at the time

   • Molecular basis of microtubule regulation not defined
   • Direct microtubule-binding partners not identified at this stage
   • Single lab, single cell context
3. 2013 Medium

   Defining SEPTIN10's septin complex membership and microtubule-associated localization placed it in a specific heteromeric assembly distinct from lamellipodial septins.

   Evidence Reciprocal immunoprecipitation and immunofluorescence co-localization in squamous carcinoma cells

   PMID:23087102

   Open questions at the time

   • Stoichiometry and filament architecture of the complex unresolved
   • Whether SEPT10 is required for complex assembly not tested
   • Functional consequence of microtubule association not addressed
4. 2017 Low

   A knockdown screen extended SEPTIN10's cytoskeletal role to a physiological cell type, showing it is required to maintain the podocyte cytoskeleton.

   Evidence siRNA knockdown with cytoskeletal injury readout in primary mouse podocytes

   PMID:28709640

   Open questions at the time

   • Single knockdown experiment without mechanistic follow-up
   • No pathway placement
   • No rescue or specificity controls reported
5. 2020 Medium

   Identifying a sperm-neck septin complex containing SEPTIN10 and linking a SEPT12 mutation to its disruption tied this assembly to connecting-piece integrity and sperm morphology.

   Evidence Co-immunoprecipitation, immunofluorescence in SEPT12 D197N knock-in mice, and electron microscopy

   PMID:32392324

   Open questions at the time

   • SEPTIN10's individual contribution versus other subunits not isolated
   • No SEPT10-specific genetic perturbation
   • Assembly mechanism at the connecting piece unresolved
6. 2022 High

   Discovering the androglobin–SEPTIN10 interaction defined an upstream regulator controlling SEPTIN10 localization and turnover during spermatogenesis.

   Evidence IP/MS, reciprocal co-IP in vitro and in testis lysates, and immunofluorescence in Adgb knockout mice

   PMID:35700329

   Open questions at the time

   • Direct proteolytic mechanism and cleavage sites not defined
   • Calmodulin dependence shown in vitro only
   • Whether proteolysis regulates septin filament dynamics in vivo unresolved
7. 2023 Medium

   Placing SEPTIN10 downstream of miR-124-3p linked its expression level to cell-fate decisions in retinal progenitor proliferation and differentiation.

   Evidence miRNA overexpression/knockdown and SEPT10 overexpression rescue with proliferation/differentiation assays in RPCs

   PMID:36802303

   Open questions at the time

   • Direct miR-124-3p:SEPT10 binding not validated in abstract
   • Cytoskeletal mechanism in RPCs not defined
   • Single lab, single context
8. 2024 High

   Identifying CAPZA2 and MAP4 as opposing SEPTIN10 partners established it as a molecular switch coordinating actin and microtubule dynamics that feeds back to YAP/TAZ mechanosignaling.

   Evidence Co-IP of SEPTIN10–CAPZA2 and SEPTIN10–MAP4, siRNA loss-of-function with cytoskeletal readouts, YAP/TAZ reporter and rescue assays in hepatocellular carcinoma cells

   PMID:38242197

   Open questions at the time

   • Whether GTPase activity gates the switch not tested
   • Structural basis of CAPZA2/MAP4 binding unknown
   • Generality beyond hepatocellular carcinoma unresolved

• How SEPTIN10's GTPase cycle, its alternative septin complex memberships, and its actin/microtubule switch activity are mechanistically integrated remains unresolved.
• No structure of SEPTIN10-containing filaments
• GTP hydrolysis not linked to partner binding or switch function
• Tissue-specific selection of distinct septin partners not explained