Affinage

FIG4

Polyphosphoinositide phosphatase · UniProt Q92562

Length
907 aa
Mass
103.6 kDa
Annotated
2026-06-09
51 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FIG4 is a magnesium-activated, PtdIns(3,5)P2-selective phosphoinositide 5-phosphatase that governs endolysosomal membrane homeostasis as an obligate component of the PIKfyve(Fab1)–VAC14–FIG4 complex (PMID:11950935, PMID:14528018, PMID:18653468). Originally defined in yeast as a Sac1-domain phosphatase that mediates turnover of PtdIns(3,5)P2 downstream of the Fab1 kinase (PMID:11950935), FIG4 binds the scaffold VAC14 directly and depends on it for membrane localization and protein stability, while VAC14 oligomerizes into a star-shaped pentamer whose legs engage both FIG4 and PIKfyve to assemble the complex on PtdIns(3)P-bearing endolysosomal membranes (PMID:14528018, PMID:18653468, PMID:40305106). Despite acting catalytically to consume PtdIns(3,5)P2, FIG4 paradoxically supports its synthesis: loss of FIG4 lowers steady-state PtdIns(3,5)P2 and PtdIns5P, and catalytically dead FIG4 still rescues much of the phenotype, establishing a phosphatase-independent scaffolding/biosynthetic role in stabilizing PIKfyve activity in addition to its catalytic turnover function (PMID:26662798, PMID:26604144, PMID:31313076). The reduced PtdIns(3,5)P2 in FIG4-deficient cells impairs TRPML1-mediated lysosomal Ca2+ efflux and de-represses the lysosomal chloride transporter ClC-7, producing enlarged, hyperacidic lysosomes through a block in lysosomal fission tied to dynamin-1 downregulation; pharmacological TRPML1 activation or genetic suppression of CLCN7 corrects these defects (PMID:25926456, PMID:37363915). In mammals FIG4 is required cell-autonomously in motor neurons and Schwann cells and non-cell-autonomously for oligodendrocyte myelination, and its loss causes spongiform neurodegeneration, axonal degeneration, and demyelination (PMID:22581779, PMID:22131434, PMID:25187576). Loss-of-function and destabilizing missense mutations such as FIG4-I41T, which disrupts VAC14 binding and triggers proteasomal degradation, cause Charcot-Marie-Tooth disease type 4J (PMID:21655088).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2002 High

    Established FIG4's core biochemical identity by asking what enzyme controls PtdIns(3,5)P2 turnover, placing it as a phosphatase downstream of the Fab1 kinase.

    Evidence Genetic epistasis/suppressor screen and lipid phosphate measurement in yeast

    PMID:11950935

    Open questions at the time
    • Did not resolve substrate selectivity or whether FIG4 acts directly on the lipid in vitro
    • Mammalian relevance not addressed
  2. 2003 High

    Defined FIG4 as a magnesium-activated, PtdIns(3,5)P2-selective phosphatase and showed Vac14 anchors it to the vacuolar membrane, beginning to assemble the complex.

    Evidence In vitro phosphatase assay, GFP localization, and co-IP in yeast

    PMID:14528018

    Open questions at the time
    • Did not include the kinase Fab1/PIKfyve in the architecture
    • Structural basis of FIG4–Vac14 binding unknown
  3. 2007 High

    Extended the yeast model to mammals, showing FIG4 is required for endosome-lysosome trafficking and that its loss causes neurodegeneration via vacuolar accumulation.

    Evidence Positional cloning, phosphoinositide measurement, and LAMP-2 imaging in the pale tremor mouse and patient cells

    PMID:17572665

    Open questions at the time
    • Cell-type basis of neurodegeneration not resolved
    • Counterintuitive accumulation of PtdIns(3,5)P2 in some assays not yet reconciled with the phosphatase role
  4. 2008 High

    Resolved the tripartite complex architecture by showing Fab1/PIKfyve joins Vac14 and Fig4 through its chaperonin-like domain, with FYVE-domain tethering to PtdIns(3)P, explaining dual synthesis/turnover.

    Evidence Reciprocal co-IP, domain-mapping pulldowns, and GFP localization in yeast

    PMID:18653468

    Open questions at the time
    • Stoichiometry and full structure not determined
    • How a phosphatase and kinase coexist productively unexplained
  5. 2008 Medium

    Connected lysosomal dysfunction to cellular consequence by showing vacuoles physically obstruct organelle trafficking and that neuronal death is non-apoptotic and non-ubiquitin-mediated.

    Evidence Time-lapse live imaging of patient fibroblasts and histology/EM of plt mouse neurons

    PMID:18556664

    Open questions at the time
    • Molecular cause of fission/trafficking block not identified
    • Single-lab observation
  6. 2011 High

    Established the disease mechanism for CMT4J by showing the I41T mutation disrupts VAC14 binding, destabilizing FIG4 and routing it to proteasomal degradation.

    Evidence Yeast two-hybrid, Western blot in VAC14-null tissue and patient fibroblasts, MG-132 rescue, transgenic mouse

    PMID:21655088

    Open questions at the time
    • Whether residual FIG4 retains partial function in patients unclear
    • Did not address phosphatase vs scaffolding contribution to disease
  7. 2011 High

    Defined the cellular site of FIG4 requirement in the nervous system, showing neuronal expression is necessary and sufficient to prevent spongiform degeneration while astrocyte expression is not.

    Evidence Cell-type-specific transgenic rescue and conditional knockout with histology and survival analysis

    PMID:22581779

    Open questions at the time
    • Did not isolate the molecular pathway downstream of neuronal FIG4 loss
  8. 2011 High

    Revealed non-cell-autonomous neuron-to-glia signaling by showing neuronal Fig4 supports CNS myelination indirectly through oligodendrocyte maturation.

    Evidence NSE-Fig4 transgenic rescue, optic nerve EM, action potential recordings, OL-marker IHC

    PMID:22131434

    Open questions at the time
    • Nature of the neuron-derived signal to oligodendrocytes unknown
  9. 2011 Medium

    Showed neuron-type-specific lysosomal pathology, distinguishing sensory neuron membrane disruption from motor neuron lysosomal protein retention.

    Evidence EM and lysosomal-marker immunofluorescence (LAMP2, NPC1, M6PR) in plt mouse neurons

    PMID:21410794

    Open questions at the time
    • Basis of neuron-type selectivity unexplained
    • Single-lab descriptive study
  10. 2012 High

    Uncovered a phosphatase-independent function by showing catalytic-dead FIG4 (and even the opposing Fab1 kinase) rescues lysosomal expansion, placing FIG4 action after endosome-lysosome fusion.

    Evidence Drosophila catalytic-dead rescue and genetic epistasis with Rab7/HOPS, LysoTracker

    PMID:26662798

    Open questions at the time
    • Molecular basis of the scaffolding/biosynthetic function not isolated
    • Mammalian confirmation pending at this stage
  11. 2014 High

    Demonstrated cell-autonomous requirements in both motor neurons and Schwann cells, linking Schwann cell FIG4 to autophagy-dependent myelin biogenesis and remyelination.

    Evidence Cell-type-specific conditional knockouts with histology, EM, and nerve conduction

    PMID:25187576

    Open questions at the time
    • Did not define which lipid pool drives each cell-type phenotype
  12. 2015 High

    Identified the fission defect mechanism, linking reduced PI(3,5)P2 to impaired TRPML1 Ca2+ efflux and dynamin-1 loss, with pharmacological TRPML1 activation rescuing lysosomal storage.

    Evidence Flow cytometry, Ca2+ assays, ML-SA1 rescue, dynamin-1 Western blot, ex vivo DRG

    PMID:25926456

    Open questions at the time
    • How dynamin-1 expression is coupled to lysosomal Ca2+ not fully mapped
  13. 2015 High

    Dissected the dual functions in mammals, showing catalytic-dead FIG4 rescues neonatal neurodegeneration (scaffolding role) but not long-term myelination/hydrocephalus (requiring catalysis).

    Evidence C486S active-site mutagenesis, fibroblast and neuronal transgenic rescue, histology, survival

    PMID:26604144

    Open questions at the time
    • Why catalysis is selectively required for long-term myelin maintenance unresolved
  14. 2017 Medium

    Identified TRPV4 as a FIG4-regulated membrane protein whose slowed turnover accumulates at the plasma membrane and contributes to neuronal death.

    Evidence TRPV4 IF/Western in patient fibroblasts, Fig4 siRNA in motor neurons, TRPV4 inhibition with viability assay

    PMID:28859335

    Open questions at the time
    • TRPV4 inhibition preserved viability without correcting trafficking, so the causal link is partial
    • Single lab
  15. 2018 High

    Established a life-long, tissue-differential requirement, showing adult PNS fibers degenerate without Fig4 while CNS fibers need it mainly for remyelination after injury.

    Evidence Inducible CAG-creER knockout, nerve histology, compound action potentials, lysolecithin lesion model

    PMID:29688489

    Open questions at the time
    • Why CNS adult fibers tolerate loss but PNS fibers do not unexplained
  16. 2019 High

    Quantified the lipid consequence in patients, showing FIG4 deficiency reduces both PtdIns(3,5)P2 and PtdIns5P, with PtdIns3P variability tracking vacuolation.

    Evidence HPLC phosphoinositide profiling in 13 patient vs 9 control fibroblasts

    PMID:31313076

    Open questions at the time
    • Source of inter-patient PtdIns3P variability not resolved
  17. 2021 High

    Solved the complex architecture, showing VAC14 forms a star-shaped pentamer whose legs bind FIG4 and PIKfyve, and that oligomerization is required for PI(3,5)P2 generation.

    Evidence AlphaFold2/cryo-EM, pull-downs in VAC14 KO cells, FSEC, VPS35 colocalization

    PMID:40305106

    Open questions at the time
    • High-resolution structure of FIG4 within the assembly still incomplete
  18. 2021 Medium

    Mapped the complex's broader interactome, linking the PIKfyve-VAC14-FIG4 complex to the COPI coat machinery (COPB1, Arf1) at endosomes.

    Evidence BioID proximity labeling and proximity ligation assay validation

    PMID:34554760

    Open questions at the time
    • BioID detects proximity, not direct binding
    • Functional consequence of COPI interface untested
  19. 2023 High

    Identified ClC-7 as a key effector, showing PI(3,5)P2 inhibits the transporter and that suppressing CLCN7 corrects lysosomal swelling and extends Fig4-null mouse lifespan.

    Evidence CLCN7/CLCN6 KO in FIG4-null cells, lysosome size/pH assays, dominant-negative CLCN7 in mice

    PMID:37363915

    Open questions at the time
    • Only partial correction of hyperacidification, indicating additional effectors
  20. 2023 High

    Defined an opposing-kinase modulator, showing Pip4k2c haploinsufficiency elevates PI(3,5)P2 and rescues Fig4-null lethality and lysosomal enlargement.

    Evidence Fig4-/- Pip4k2c+/- compound mutant mice, fibroblast lysosome measurement, survival

    PMID:36691351

    Open questions at the time
    • Mechanism of PIP4K2C control over the PI(3,5)P2 pool not detailed
  21. 2025 Medium

    Uncovered a complex- and catalysis-independent role in TORC1 signaling, where Fig4 mutants confer rapamycin tolerance through the kinase Ste20.

    Evidence Yeast point-mutant genetics, vac14Δ/ste20Δ epistasis, rapamycin growth assays

    PMID:40741910

    Open questions at the time
    • The unknown partners mediating this function are unidentified
    • Mammalian relevance untested
  22. 2026 Medium

    Extended FIG4 into cancer cell biology, showing FIG4 overexpression drives LAMP2A-dependent autophagic-lysosomal degradation and ubiquitination of IL-18.

    Evidence FIG4 overexpression/knockdown, IL-18 Western/ELISA, degradation and ubiquitination assays in TNBC lines

    PMID:41577074

    Open questions at the time
    • No reconstitution or structural validation
    • Direct vs indirect effect on IL-18 turnover unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FIG4's catalytic and scaffolding functions are differentially deployed across cell types and how the complex selectively maintains PI(3,5)P2 pools for distinct effectors (TRPML1, ClC-7) remains unresolved.
  • No high-resolution structure of FIG4 within the assembled complex
  • Mechanism coupling lipid changes to dynamin-1 and TRPV4 turnover incompletely defined
  • Complex-independent FIG4 functions (TORC1, IL-18) mechanistically unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 3 GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3 R-HSA-9612973 Autophagy 2 R-HSA-162582 Signal Transduction 1
Partners
ARF1COPB1PIKFYVEVAC14
Complex memberships
PIKfyve-VAC14-FIG4 (PAS) complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Fig4 (Sac1 domain-containing protein) functions as a phosphoinositide phosphatase that mediates turnover of PtdIns(3,5)P2; deletion of FIG4 in vac7Δ yeast suppresses temperature sensitivity, vacuolar morphology defects, and dramatically restores PtdIns(3,5)P2 levels, placing Fig4 as a negative regulator (phosphatase) acting downstream of Fab1 kinase in the PtdIns(3,5)P2 pathway. Genetic epistasis (suppressor screen, deletion analysis), lipid phosphate measurements in yeast Molecular biology of the cell High 11950935
2003 Fig4 is a magnesium-activated, PtdIns(3,5)P2-selective phosphoinositide phosphatase in vitro; it localizes to the vacuolar limiting membrane via interaction with the scaffold protein Vac14, and Vac14 is required for Fig4 vacuolar localization. Fig4 physically associates with Vac14 in a common membrane-associated complex. In vitro phosphatase assay, GFP-localization imaging, co-immunoprecipitation, deletion analysis in yeast Molecular biology of the cell High 14528018
2007 Mammalian FIG4 is the functional homologue of yeast Fig4; loss of Fig4 in the pale tremor mouse leads to abnormal accumulation of PtdIns(3,5)P2 in cultured fibroblasts and LAMP-2-positive vacuoles consistent with dysfunction of the late endosome-lysosome axis, establishing FIG4 as a PtdIns(3,5)P2 5-phosphatase required for endosome-lysosome membrane trafficking in mammals. Positional cloning, phosphoinositide measurement in fibroblasts, immunofluorescence for LAMP-2, mouse null model Nature High 17572665
2008 Fab1 (PIKfyve) binds to Vac14 and Fig4 through its chaperonin-like domain to form a vacuole-associated signaling complex; the complex is tethered to the vacuole via interaction between the FYVE domain in Fab1 and PtdIns(3)P. Vac14 and Fig4 bind each other directly and are mutually dependent for interaction with Fab1, explaining their dual roles in both synthesis and turnover of PtdIns(3,5)P2. Co-immunoprecipitation, domain-mapping pulldown assays, GFP localization in yeast Molecular biology of the cell High 18653468
2008 FIG4 deficiency leads to impaired trafficking of intracellular organelles in patient fibroblasts, demonstrated by time-lapse imaging showing physical obstruction by vacuoles; axonal degeneration in motor and sensory neurons occurs without TUNEL staining or accumulation of ubiquitinated protein in vacuoles. Time-lapse live imaging of fibroblasts, histology and electron microscopy of plt mouse neurons Brain : a journal of neurology Medium 18556664
2011 The CMT4J-causing FIG4-I41T missense mutation impairs interaction of FIG4 with the scaffold protein VAC14 (shown by yeast two-hybrid), causing protein instability and proteasomal degradation; VAC14 binding is required for FIG4 protein stability in vivo, as FIG4 protein is absent in VAC14 null mouse tissues. Treatment with proteasome inhibitor MG-132 increases FIG4-I41T abundance in cultured cells. Yeast two-hybrid, Western blot in mouse tissues and patient fibroblasts, proteasome inhibitor treatment, transgenic mouse model PLoS genetics High 21655088
2011 Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration; conditional neuron-specific deletion of Fig4 (via Synapsin-Cre) recapitulates full spongiform degeneration and lethality, while astrocyte-specific expression prevents autophagy marker accumulation and microgliosis but not spongiform degeneration. Transgenic rescue (NSE-promoter, GFAP-promoter), conditional knockout (floxed allele x Synapsin-Cre), histology, survival analysis Human molecular genetics High 22581779
2011 Fig4 deficiency leads to distinct pathological changes in different neuron types: sensory neurons (DRG) accumulate vacuoles with membrane disruption from postnatal day 4, whereas spinal motor neurons accumulate electron-dense organelles with elevated LAMP2 and NPC1 (lysosomal proteins) but not mannose-6-phosphate receptor, indicating excessive retention of molecules within lysosomes. Electron microscopy, immunofluorescence for lysosomal markers (LAMP2, NPC1, M6PR) in plt mouse neurons The European journal of neuroscience Medium 21410794
2011 Fig4 null mice exhibit dramatic reduction of CNS myelin; neuronal (neuron-specific) expression of Fig4 is sufficient to rescue CNS myelination and tremor through a non-cell-autonomous mechanism on oligodendrocyte maturation, demonstrating that Fig4 in neurons supports OL development indirectly. Transgenic rescue (NSE-Fig4), electron microscopy of optic nerve, action potential recordings, immunohistochemistry for OL markers The Journal of neuroscience High 22131434
2012 In Drosophila, Fig4 mutations predicted to inactivate phosphatase activity can rescue lysosomal expansion phenotypes, as can mutations in the opposing kinase Fab1, demonstrating that FIG4 serves a phosphatase-independent (biosynthetic/scaffolding) function essential for lysosomal membrane homeostasis. Lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, placing FIG4 function after endosome-to-lysosome fusion. Drosophila transgenic rescue with catalytic-dead alleles, genetic epistasis (Rab7, HOPS, retromer mutants), LysoTracker staining Human molecular genetics High 26662798
2014 Fig4 has cell-autonomous roles in both motor neurons and Schwann cells: conditional inactivation in motor neurons causes neuronal and axonal degeneration, while conditional inactivation in Schwann cells causes demyelination and defects in autophagy-mediated degradation; Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis and remyelination after injury. Cell-type-specific conditional knockout (Cre-lox in motor neurons and Schwann cells), histology, electron microscopy, nerve conduction studies Human molecular genetics High 25187576
2015 FIG4 deficiency impairs lysosomal fission (but not fusion) associated with increased intralysosomal Ca2+; this is mechanistically linked to reduced PI(3,5)P2 availability for the TRPML1 lysosomal Ca2+ channel. Reactivation of TRPML1 with synthetic ligand ML-SA1 reduces intralysosomal Ca2+, rescues lysosomal storage in FIG4-deficient cells and ex vivo DRGs, and restores dynamin-1 expression/activity required for lysosomal membrane fission. Flow cytometry (lysosome size), Ca2+ measurements, pharmacological TRPML1 activation (ML-SA1), Western blot for dynamin-1, ex vivo DRG rescue The Journal of neuroscience High 25926456
2015 A catalytically inactive FIG4 (p.Cys486Ser, active-site CX5RT motif mutated) prevents vacuolization in cultured Fig4−/− fibroblasts and rescues neonatal neurodegeneration and juvenile lethality in vivo when expressed neuronally, demonstrating that FIG4's scaffolding/complex-stabilization function (independent of phosphatase activity) provides significant in vivo function. However, late-onset hydrocephalus, defective myelination, and reduced lifespan in these mice demonstrates that phosphatase activity is also required for full long-term function. Active-site mutagenesis (C486S), transfection rescue assay in fibroblasts, in vivo neuronal transgenic rescue, histology, survival analysis Human molecular genetics High 26604144
2017 FIG4 deficiency causes slow turnover of the membrane protein TRPV4, leading to its accumulation at the plasma membrane of patient fibroblasts; knockdown of Fig4 in murine motor neurons caused vacuolation and cell death, and inhibiting TRPV4 activity significantly preserved neuron viability (though without correcting vesicular trafficking), demonstrating a functional interaction between FIG4 and TRPV4. Immunofluorescence/Western blot of TRPV4 in patient fibroblasts, siRNA knockdown of Fig4 in motor neurons, pharmacological TRPV4 inhibition with viability assay Journal of neuropathology and experimental neurology Medium 28859335
2018 Global adult inactivation of Fig4 (tamoxifen-inducible CAG-creER) leads to progressive Wallerian degeneration of myelinated PNS fibers, demonstrating a life-long requirement for Fig4 in protecting myelinated axons. In the CNS, adult Fig4 is dispensable for fiber stability under normal conditions but is required for timely remyelination after a chemical white matter lesion. Inducible conditional knockout (tamoxifen-CAG-creER), histology of sciatic and optic nerve, compound action potential recordings, lysolecithin white matter lesion model Human molecular genetics High 29688489
2019 In CMT4J patient fibroblasts, SAC3/FIG4 deficiency reduces steady-state PtdIns(3,5)P2 by 36% and PtdIns5P by 43% relative to controls, as measured by HPLC lipid profiling; PtdIns3P levels were variable across individual patients and correlated with presence of aberrant endolysosomal vacuoles. HPLC phosphoinositide profiling after myo-[2-3H]inositol labeling in patient fibroblasts, Western blot for FIG4 protein Molecular neurobiology High 31313076
2021 VAC14 forms a star-shaped pentamer scaffold where two legs bind FIG4 (with one leg also occupied by PIKfyve); VAC14 oligomerization is critical for Fab1/PIKfyve function, PI(3,5)P2 generation, VAC14 localization, and formation of the PIKfyve-VAC14-FIG4 complex as assessed by pull-down assays; patient mutations at VAC14-VAC14 interfaces disrupt oligomerization and complex assembly. AlphaFold2 structural prediction, cryo-EM maps, pull-down assays in human VAC14 KO cells, fluorescence-detection size-exclusion chromatography, colocalization with VPS35 endosomes Molecular biology of the cell High 40305106
2021 Proximity interactome (BioID) of VAC14 and FIG4 identified 89 high-confidence shared interactors; proximity ligation assays validated interaction between VAC14 and COPI subunit COPB1 and between VAC14 and the GTPase Arf1 (required for COPI assembly), suggesting the PIKfyve-VAC14-FIG4 complex interfaces with the COPI coat machinery at endosomes. BioID proximity labeling, proximity ligation assay, mass spectrometry Journal of proteome research Medium 34554760
2023 PI(3,5)P2 inhibits the lysosomal chloride transporter ClC-7; loss of FIG4 (or VAC14) reduces PI(3,5)P2 and de-represses ClC-7, contributing to lysosomal swelling and hyperacidification. Knockout of CLCN7 (but not the related CLCN6) corrects lysosomal swelling and partially corrects lysosomal hyperacidification in FIG4-null cells; in vivo, dominant-negative CLCN7 expression improves growth, neurological function, and lifespan in Fig4 null mice by ~20%. CLCN7 and CLCN6 knockout in FIG4-null cell culture, lysosome size and pH measurements, transgenic dominant-negative CLCN7 in Fig4 null mice, survival and behavioral analysis PLoS genetics High 37363915
2023 FIG4-regulated PI(3,5)P2 biosynthesis genetically interacts with the phosphoinositide kinase PIP4K2C: haploinsufficiency of Pip4k2c (which elevates PI(3,5)P2) rescues the neonatal lethality of Fig4 null mice and reduces lysosomal enlargement in Fig4 null cells, demonstrating that the opposing kinase PIP4K2C modulates the FIG4 pathway in vivo. Genetic compound mutant mice (Fig4-/-, Pip4k2c+/-), lysosome size measurement in fibroblasts, survival analysis G3 (Bethesda, Md.) High 36691351
2025 Fig4 mutants that fail to bind the Fab1-Vac14-Fig4 complex confer tolerance to rapamycin (TORC1 inhibitor) in yeast independent of Fig4 catalytic activity and Vac14 scaffolding, requiring instead the p21-activated kinase Ste20, demonstrating that Fig4 can modulate TORC1 signaling through a complex-independent, catalysis-independent interaction with unknown partners. Yeast genetics (point mutations, vac14Δ epistasis), rapamycin growth assays, temperature-shift experiments, kinase deletion (ste20Δ) Molecular microbiology Medium 40741910
2026 FIG4 overexpression promotes LAMP2A-dependent autophagy-lysosomal degradation of IL-18 and enhances ubiquitination of IL-18, reducing its secretion; FIG4 thus functions as a regulator of IL-18 autophagic-lysosomal turnover in cancer cells. Overexpression and knockdown of FIG4, Western blot/ELISA for IL-18, lysosomal degradation assays, ubiquitination assays in triple-negative breast cancer cell lines Cancer letters Medium 41577074

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 414 17572665
2003 Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. Molecular biology of the cell 163 14528018
2002 Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4, a polyphosphoinositide phosphatase family member. Molecular biology of the cell 136 11950935
2008 Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain : a journal of neurology 115 18556664
2008 Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase. Molecular biology of the cell 110 18653468
2011 Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS genetics 90 21655088
2014 Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology 73 24598713
2017 FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study. European journal of human genetics : EJHG 57 28051077
2012 Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration. Human molecular genetics 53 22581779
2015 Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 25926456
2014 Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy. Human molecular genetics 44 25187576
2015 FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Human molecular genetics 43 26662798
2011 Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 22131434
2011 Distinct pathogenic processes between Fig4-deficient motor and sensory neurons. The European journal of neuroscience 38 21410794
2021 AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model. The Journal of clinical investigation 33 33878035
2015 Knockdown of the Drosophila FIG4 induces deficient locomotive behavior, shortening of motor neuron, axonal targeting aberration, reduction of life span and defects in eye development. Experimental neurology 30 26708557
2012 Fig4 deficiency: a newly emerged lysosomal storage disorder? Progress in neurobiology 30 23165282
2018 Genetic screening of the genes interacting with Drosophila FIG4 identified a novel link between CMT-causing gene and long noncoding RNAs. Experimental neurology 28 30165075
2020 FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome. Parkinsonism & related disorders 27 32268254
2019 Cerebral hypomyelination associated with biallelic variants of FIG4. Human mutation 27 30740813
2013 ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases. Neuropathology : official journal of the Japanese Society of Neuropathology 25 23888880
2018 Protective role of the lipid phosphatase Fig4 in the adult nervous system. Human molecular genetics 20 29688489
2013 Novel FIG4 mutations in Yunis-Varon syndrome. Journal of human genetics 18 24088667
2015 Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene. Human molecular genetics 16 26604144
2014 Whole exome sequencing identifies three recessive FIG4 mutations in an apparently dominant pedigree with Charcot-Marie-Tooth disease. Neuromuscular disorders : NMD 15 24878229
2023 The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG4 and VAC14 mutants. PLoS genetics 14 37363915
2020 Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy. Clinical genetics 13 32385905
2017 A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade. Journal of neuropathology and experimental neurology 12 28859335
2012 Fig4 expression in the rodent nervous system and its potential role in preventing abnormal lysosomal accumulation. Journal of neuropathology and experimental neurology 12 22157617
2023 Clinical and genetic features of patients suffering from CMT4J. Journal of neurology 11 37950760
2022 Novel Variants in the FIG4 Gene Associated With Chinese Sporadic Amyotrophic Lateral Sclerosis With Slow Progression. Journal of clinical neurology (Seoul, Korea) 10 35021275
2019 Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J. Molecular neurobiology 10 31313076
2022 Case report: A variant of the FIG4 gene with rapidly progressive amyotrophic lateral sclerosis. Frontiers in neurology 9 36090855
2021 FIG4-Associated Yunis-Varon Syndrome: Identification of a Novel Missense Variant. Molecular syndromology 9 34899148
2022 Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice. Molecular genetics and metabolism 8 36434903
2021 Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients. Annals of clinical and translational neurology 8 33405357
2019 Epigallocatechin gallate enhances the motor neuron survival and functional recovery after brachial plexus root avulsion by regulating FIG4. Folia neuropathologica 8 32337947
2024 FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature. Genes 7 39457468
2021 Proximity Interactome Map of the Vac14-Fig4 Complex Using BioID. Journal of proteome research 6 34554760
2013 Murine Fig4 is dispensable for muscle development but required for muscle function. Skeletal muscle 6 24004519
2023 Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c. G3 (Bethesda, Md.) 5 36691351
2015 FIG4 is a hepatitis C virus particle-bound protein implicated in virion morphogenesis and infectivity with cholesteryl ester modulation potential. The Journal of general virology 5 26519381
2022 Case report and literature review: Novel compound heterozygous FIG4 variants causing both of peripheral and central nervous system defects. Frontiers in pediatrics 4 36340727
2022 T2 olivary nuclei hyperintensities: A characteristic neuroimaging finding in FIG4-related leukoencephalopathy. American journal of medical genetics. Part A 4 36529678
2020 Case Report: Association of a Variant of Unknown Significance in the FIG4 Gene With Frontotemporal Dementia and Slowly Progressing Motoneuron Disease: A Case Report Depicting Common Challenges in Clinical and Genetic Diagnostics of Rare Neuropsychiatric and Neurologic Disorders. Frontiers in neuroscience 4 33424531
2025 VAC14 oligomerization is essential for the function of the FAB1/PIKfyve-VAC14-FIG4 complex. Molecular biology of the cell 3 40305106
2022 Clinical and Genetic Analysis of a Patient with CMT4J. Neurology international 3 35225887
2026 FIG4 downregulation-arrested autophagy-lysosomal degradation of IL-18 drives lipid-associated macrophage polarization and immunotherapy resistance in triple-negative breast cancer. Cancer letters 2 41577074
2025 Phenotypic spectrum of variants in the FIG4 gene: variants associated with Charcot-Marie-Tooth 4J and parkinsonism. European journal of medical genetics 2 41177402
2025 Homeostatic Influence of Fig4 Outside of the Fab1-Vac14-Fig4 Complex in Saccharomyces cerevisiae. Molecular microbiology 1 40741910
2025 Identification and splicing analysis of the first deep intronic FIG4 variant causing Yunis-Varon syndrome. Frontiers in genetics 0 40860339

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