Affinage

CLIC1

Chloride intracellular channel protein 1 · UniProt O00299

Length
241 aa
Mass
26.9 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLIC1 is a metamorphic chloride intracellular channel protein that reversibly transitions between a soluble GST-fold monomer and a membrane-inserted oligomeric ion channel, functioning in innate immunity, cell division, and tumor cell migration. The soluble form adopts a glutathione S-transferase/glutaredoxin-like fold with a redox-active Cys24–Cys59 pair whose oxidation triggers a major conformational change exposing hydrophobic surfaces that drive spontaneous membrane insertion and oligomerization into chloride-selective channels, a process further facilitated by low pH destabilization of the N-terminal transmembrane helix and membrane cholesterol (PMID:11551966, PMID:14613939, PMID:11940526, PMID:18850721, PMID:23457643). In macrophages and dendritic cells, CLIC1 translocates to phagosomal and plasma membranes upon activation, where it supports phagosomal acidification, proteolysis, NADPH oxidase redistribution for ROS generation, and NLRP3 inflammasome priming; CLIC1 knockout mice are protected from inflammatory arthritis and acute tissue injury (PMID:22956539, PMID:27113959, PMID:28275112, PMID:28576828). In migrating tumor cells, CLIC1 recruits PIP5K1A/C to the plasma membrane leading edge to generate PIP2-rich domains that promote integrin-mediated adhesion, and its channel activity at the G1–S transition regulates glioblastoma stem cell proliferation (PMID:33079727, PMID:25361004).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    Establishing that CLIC1 is itself a chloride channel — not merely a channel accessory — resolved a key question about the CLIC family's molecular identity, showing recombinant CLIC1 alone suffices for Cl⁻-selective conductance in artificial bilayers and in transfected cells with defined transmembrane topology.

    Evidence Bacterial expression and reconstitution into lipid vesicles/bilayers with single-channel recording; epitope-tagged constructs with antibody topology mapping and patch clamp in CHO-K1 cells

    PMID:10834939 PMID:10874038

    Open questions at the time
    • Exact stoichiometry of the functional channel pore not determined
    • No high-resolution structure of the membrane-inserted form
  2. 2001 High

    The crystal structure of soluble CLIC1 revealed a GST/glutaredoxin fold with a redox-active site and glutathione binding, providing the structural framework to understand how a soluble protein could rearrange for membrane insertion.

    Evidence X-ray crystallography at 1.4 Å resolution with glutathione co-crystal

    PMID:11551966

    Open questions at the time
    • Structure of the membrane-inserted conformer remained unknown
    • Role of glutathione binding in channel regulation unclear
  3. 2002 High

    Demonstration that soluble CLIC1 spontaneously inserts into preformed lipid bilayers in a pH-dependent manner, forming channels that transition from small to large conductance states suggestive of tetrameric assembly, established the paradigm of CLIC1 as a self-inserting channel protein.

    Evidence Chloride efflux assays with preformed vesicles, planar lipid bilayer electrophysiology at varying pH, comparison with CHO cell recordings

    PMID:11940526 PMID:11978800

    Open questions at the time
    • Direct measurement of oligomeric stoichiometry in membranes lacking
    • Molecular triggers for insertion in living cells not identified
  4. 2003 High

    Solving the oxidized CLIC1 structure revealed that Cys24–Cys59 disulfide formation drives a monomer-to-dimer transition exposing a large hydrophobic surface, explaining how oxidative conditions promote membrane insertion and channel activity.

    Evidence X-ray crystallography of oxidized dimer, site-directed mutagenesis of Cys24/Cys59, bilayer reconstitution under reducing vs. oxidizing conditions

    PMID:14613939

    Open questions at the time
    • Whether the oxidized dimer is the direct precursor to the membrane-inserted oligomer was not proven
    • In vivo relevance of oxidation-driven insertion not yet tested
  5. 2004 High

    Linking CLIC1 to neuroinflammation, beta-amyloid was shown to upregulate CLIC1 plasma membrane conductance in microglia, with CLIC1 knockdown preventing TNF-α release and co-cultured neuronal apoptosis — the first demonstration of a pathophysiological role for CLIC1 channel activity.

    Evidence Electrophysiology, siRNA knockdown, IAA-94 pharmacological blockade, microglia-neuron co-culture

    PMID:15190104

    Open questions at the time
    • Mechanism of CLIC1 upregulation by Aβ not defined
    • Whether CLIC1 channel activity or a non-channel function mediates TNF-α release not resolved
  6. 2005 High

    Identification of Cys24 on the extracellular/luminal face of membrane-inserted CLIC1 as the key redox sensor regulating channel amplitude established that intersubunit disulfide bonds modulate the open channel, linking redox environment to conductance.

    Evidence Planar bilayer electrophysiology with Cys24 mutagenesis and covalent modification under controlled redox potentials

    PMID:16339885

    Open questions at the time
    • No direct structural evidence for intersubunit disulfide bonds in the membrane form
    • Physiological redox potentials at relevant membrane surfaces not characterized
  7. 2008 High

    Two converging advances clarified the biophysics and cell biology of CLIC1 membrane insertion: acidic pH was shown to destabilize the N-domain transmembrane helix (lowering the insertion energy barrier), while in microglia, Aβ-induced CLIC1 translocation to the plasma membrane was shown to sustain NADPH oxidase-dependent ROS in a feedforward loop.

    Evidence Equilibrium unfolding/CD spectroscopy as a function of pH; live-cell imaging, siRNA, electrophysiology, and ROS measurements in microglia

    PMID:18850721 PMID:18987185

    Open questions at the time
    • Whether pH-induced destabilization and oxidation-driven insertion are sequential or independent triggers in vivo unclear
    • Identity of the CLIC1-NADPH oxidase physical interaction not established
  8. 2009 Medium

    Hydrogen-deuterium exchange mass spectrometry pinpointed the specific segments of domain 1 (residues 11–31 including helix α1, and 68–82) that become conformationally flexible at acidic pH, providing residue-level mapping of the pH-primed insertion-competent state.

    Evidence DXMS at pH 7.0 vs. 5.5

    PMID:19650640

    Open questions at the time
    • No accompanying functional data showing these segments directly enter the bilayer
    • Single laboratory study
  9. 2011 High

    FRET-based distance measurements showed that upon membrane interaction, CLIC1 undergoes large-scale N–C domain separation with the N-domain inserting as an extended α-helix and oxidation promoting 6–8 subunit oligomers, providing the most detailed model of the membrane-inserted architecture.

    Evidence Intramolecular and intermolecular FRET spectroscopy with lipid vesicles under oxidizing conditions

    PMID:20507120 PMID:22082111

    Open questions at the time
    • No high-resolution structure of the membrane-inserted oligomer
    • Exact subunit stoichiometry (tetramer vs. hexamer vs. octamer) unresolved
  10. 2012 High

    CLIC1 knockout mice revealed that CLIC1 translocates to phagosomal membranes in macrophages and is required for phagosomal acidification, proteolysis, and ROS production; protection of knockout mice from inflammatory arthritis established the first in vivo immune phenotype.

    Evidence CLIC1 knockout mice, pH-sensitive live imaging of phagosomes, superoxide assays, K/BxN serum-transfer arthritis model

    PMID:22956539

    Open questions at the time
    • Whether CLIC1 ion channel activity per se or a scaffolding function drives phagosomal acidification not distinguished
    • Contribution of other CLIC family members to phagosomal function not excluded
  11. 2013 High

    Mutagenesis of charged pore-lining residues (R29A altering open probability, K37A altering conductance) provided the strongest evidence that CLIC1 itself lines the ion conduction pathway, while cholesterol was identified as a membrane-composition determinant of insertion efficiency.

    Evidence Site-directed mutagenesis with tip-dip bilayer and patch-clamp recording in HEK cells; Langmuir monolayer and impedance spectroscopy with cholesterol-containing membranes

    PMID:23457643 PMID:24058583

    Open questions at the time
    • No pore structure to map R29 and K37 positions definitively
    • Cholesterol dependence not tested in native cell membranes
  12. 2014 High

    CLIC1 channel activity was shown to be preferentially active at the G1–S transition in glioblastoma stem cells and to be the direct molecular target of metformin's antiproliferative effect (via R29 in the pore), linking CLIC1 to cancer stem cell proliferation control.

    Evidence Perforated patch clamp across cell cycle, R29A mutagenesis, siRNA, proliferation and cell cycle analysis in patient-derived GBM stem cells

    PMID:25361004

    Open questions at the time
    • Mechanism by which Cl⁻ flux controls G1–S progression not defined
    • Metformin selectivity for CLIC1 over other targets not fully excluded
  13. 2016 High

    Extension of the phagosomal role to dendritic cells showed CLIC1 knockout impairs antigen processing and MHC presentation, with reduced EAE severity in vivo, broadening CLIC1's immune function beyond macrophages to adaptive immunity initiation.

    Evidence CLIC1 knockout BMDCs, phagosomal pH measurement, antigen processing assays, MOG-induced EAE model

    PMID:27113959

    Open questions at the time
    • Whether CLIC1 affects cross-presentation pathways not tested
    • Relative contributions of acidification vs. ROS to antigen processing not separated
  14. 2017 High

    Two studies established distinct CLIC1 roles in macrophage inflammatory responses: CLIC1 is required for NADPH oxidase redistribution to the plasma membrane for superoxide production (with knockout mice protected from acute tissue injury), and CLIC1 translocates to the nucleus upon LPS stimulation to participate in both IL-1β transcriptional priming and NLRP3 inflammasome assembly.

    Evidence CLIC1 knockout macrophages with NADPH oxidase localization and superoxide assays, acute injury models; confocal microscopy, cell fractionation, siRNA, ELISA, ASC speck assays in BMDMs

    PMID:28275112 PMID:28576828

    Open questions at the time
    • Whether CLIC1's nuclear function involves channel activity or a separate scaffolding role is unknown
    • Direct physical interaction between CLIC1 and NADPH oxidase subunits not demonstrated
  15. 2019 Medium

    CLIC1 was found to cooperate with CLIC4 at the cleavage furrow during cytokinesis, with combined knockout causing furrow regression and multinucleation, revealing a non-redundant role in cell division beyond G1–S.

    Evidence CLIC4/CLIC1 double knockout cells, live-cell imaging, Co-IP with ezrin/anillin/ALIX

    PMID:31879279

    Open questions at the time
    • CLIC1-specific contribution at the cleavage furrow not separated from CLIC4
    • Whether channel activity or scaffolding drives cytokinesis function unclear
  16. 2021 High

    Two studies revealed CLIC1's roles in signaling at the plasma membrane: it recruits PIP5K1A/C to generate PIP2-rich domains for integrin-mediated adhesion and tumor metastasis, and it mediates S1P-induced RhoA activation (via S1PR2/3) and Rac1 activation (via S1PR1) for endothelial barrier function — functions not interchangeable with CLIC4.

    Evidence Comparative proteomics, Co-IP, live-cell imaging, mouse metastasis model, PIP2 staining; siRNA, GTPase activation assays, transendothelial resistance in endothelial cells

    PMID:33079727 PMID:33879602

    Open questions at the time
    • Whether PIP5K recruitment requires CLIC1 channel activity or protein-protein interaction not distinguished
    • Structural basis for CLIC1 vs. CLIC4 non-redundancy unknown
  17. 2024 Medium

    Matrix stiffness was shown to transcriptionally upregulate CLIC1 via Wnt/β-catenin/TCF4, with CLIC1 then stabilizing HIF1α by ROS-mediated inhibition of hydroxylation to promote glycolytic metabolism in pancreatic cancer, linking mechanotransduction to metabolic reprogramming through CLIC1.

    Evidence In vitro stiffness manipulation, Wnt pathway analysis, HIF1α hydroxylation assay, ROS measurement, siRNA/overexpression in PDAC cells

    PMID:39154343

    Open questions at the time
    • Whether CLIC1-generated ROS requires its channel activity or an enzymatic function not clarified
    • Single laboratory finding in one cancer type

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the membrane-inserted CLIC1 channel, definitive oligomeric stoichiometry, and discrimination of channel-dependent versus channel-independent (scaffolding) functions across its diverse cellular roles remain central unresolved questions.
  • No atomic-resolution structure of the membrane-inserted oligomeric channel
  • Channel vs. scaffolding function not separated for phagosomal, nuclear, or PIP5K recruitment roles
  • Mechanism coupling Cl⁻ conductance to cell cycle progression undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7 GO:0008289 lipid binding 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 4 GO:0005634 nucleus 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-382551 Transport of small molecules 4 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3
Partners
CLIC4EZRITGB3PIP5K1APIP5K1C

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Crystal structure of soluble CLIC1 at 1.4 Å resolution reveals a monomeric protein structurally homologous to the glutathione S-transferase superfamily with a redox-active site resembling glutaredoxin; co-crystal with glutathione shows glutathione occupying the redox-active site adjacent to a basic-residue-lined slot, with the N-domain (residues 1–90) proposed to undergo major structural rearrangement for membrane integration involving the putative transmembrane helix near the redox-active site. X-ray crystallography (1.4 Å resolution), glutathione co-crystal structure The Journal of biological chemistry High 11551966
2003 On oxidation, CLIC1 undergoes a reversible transition from monomer to non-covalent dimer via formation of an intramolecular disulfide bond between Cys-24 and Cys-59; the oxidized dimer crystal structure reveals a major conformational change exposing a large hydrophobic surface that forms the dimer interface; the oxidized dimer retains chloride channel activity in artificial bilayers/vesicles, while reducing conditions prevent channel formation; mutagenesis shows both Cys-24 and Cys-59 are required for channel activity. X-ray crystallography of oxidized form, in vitro lipid bilayer and vesicle reconstitution, site-directed mutagenesis (Cys24, Cys59) The Journal of biological chemistry High 14613939
2000 CLIC1 (NCC27) forms a chloride-selective ion channel on both plasma and nuclear membranes in transfected CHO-K1 cells; antibody-epitope tagging experiments demonstrate CLIC1 is a transmembrane protein with the amino terminus projecting outward and the carboxyl terminus inward, establishing CLIC1 as directly forming part of the ion channel complex. Electrophysiology (patch clamp), epitope-tagged constructs with selective antibody inhibition, transfection in CHO-K1 cells FASEB journal High 10834939
2000 CLIC1 (NCC27) chloride conductance is selectively expressed on the plasma membrane of cells in G2/M phase of the cell cycle; chloride channel blockers known to block NCC27 arrest CHO-K1 cells in G2/M, implicating CLIC1 in cell cycle regulation. Electrophysiology across cell cycle stages, pharmacological blockade with cell cycle analysis The Journal of physiology Medium 11195932
2000 Recombinant CLIC-1 expressed in bacteria and reconstituted into phospholipid vesicles forms a voltage-dependent, Cl-selective channel (conductances 161 and 67.5 pS in 300 and 150 mM KCl) with anion selectivity Br ≈ Cl > I, inhibited by IAA-94; demonstrates CLIC-1 forms a chloride channel in the absence of other subunits. Bacterial expression, phospholipid vesicle reconstitution (valinomycin-dependent Cl efflux assay), planar lipid bilayer electrophysiology, pharmacology The Journal of biological chemistry High 10874038
2002 Soluble CLIC1 in the absence of detergent spontaneously inserts into preformed phospholipid membranes and functions as an anion channel; channel activity is dependent on CLIC1 amount, inhibited by IAA-94, NEM, and glutathione, sensitive to pH and membrane lipid composition, and appears rapidly upon mixing protein and lipid vesicles. Chloride efflux assay with preformed vesicles, planar lipid bilayer electrophysiology, pharmacology American journal of physiology. Cell physiology High 11940526
2002 Membrane integration of CLIC1 is pH-dependent; small conductance channels with slow kinetics (SCSK) form first and then transition to high-conductance fast-kinetic channels with ~4-fold higher conductance, suggesting the functional CLIC1 channel is a tetrameric assembly of subunits; channels in bilayers are identical in conductance, pharmacology, and kinetics to those in CLIC1-transfected CHO cells. Planar lipid bilayer electrophysiology, pH-dependence studies, comparison with CHO cell recordings The Journal of biological chemistry High 11978800
2005 Redox potential on the extracellular/luminal side of the membrane regulates CLIC1 channel amplitude; Cys-24 in a cysteine-proline motif is a critical redox-sensitive residue located on the extracellular/luminal side of membrane-inserted CLIC1, near the putative channel pore; covalent modification and site-directed mutagenesis of Cys-24 support a model of intersubunit disulfide bond formation/reduction regulating channel activity. Planar lipid bilayer electrophysiology, site-directed mutagenesis (Cys24), covalent functional modification, redox potential manipulation Biophysical journal High 16339885
2007 CLIC1 and CLIC5, but not CLIC4, are strongly and reversibly inhibited by cytosolic F-actin in planar lipid bilayers in the absence of any other protein; disrupting F-actin with cytochalasin reverses the inhibition, establishing a direct regulatory interaction between F-actin and membrane-inserted CLIC1. Planar lipid bilayer electrophysiology with purified recombinant CLICs, F-actin addition and cytochalasin-mediated F-actin disruption The FEBS journal High 18028448
2004 Beta-amyloid stimulation of rat microglia increases CLIC1 protein expression and functional CLIC1 chloride conductance at the plasma membrane; CLIC1 channel blockade with IAA-94 prevents neuronal apoptosis in co-culture; CLIC1 siRNA knockdown prevents TNF-alpha release induced by Aβ, establishing a direct link between Aβ-induced microglial activation and CLIC1 functional expression. Electrophysiology, siRNA knockdown, pharmacological blockade (IAA-94), co-culture neurotoxicity assay, ELISA for TNF-α The Journal of neuroscience High 15190104
2008 Beta-amyloid promotes acute translocation of CLIC1 from cytosol to plasma membrane of microglia; membrane-inserted CLIC1 mediates a chloride conductance required for Aβ-induced NADPH oxidase-dependent ROS generation; CLIC1 activation is itself dependent on oxidation by NADPH oxidase-derived ROS, establishing a feedforward mechanism for sustained ROS generation; blocked by anti-CLIC1 antibody, siRNA, and Cl- replacement. Live-cell imaging, siRNA knockdown, electrophysiology, ROS measurement, pharmacological inhibition, anti-CLIC1 antibody, anion replacement The Journal of neuroscience High 18987185
2011 FRET studies demonstrate that CLIC1 undergoes a large-scale conformational unfolding between N- and C-domains upon membrane interaction; the N-terminal domain inserts into the bilayer as an extended α-helix; under oxidative conditions CLIC1 forms oligomers upon membrane interaction consistent with a 6–8 subunit transmembrane assembly. FRET spectroscopy (inter- and intramolecular), oxidative conditions, lipid vesicle interaction, oligomer modeling Biochemistry High 22082111
2010 FRET spectroscopy reveals a large conformational unfolding between N- and C-domains of CLIC1 upon membrane vesicle interaction, consistent with the N-terminal domain inserting into the lipid bilayer while the C-domain remains on the extravesicular surface. FRET spectroscopy, lipid vesicle interaction, fluorescent labeling of CLIC1 Biochemistry Medium 20507120
2008 Acidic pH destabilizes CLIC1 by forming a highly populated intermediate with exposed hydrophobic surface; the intermediate involves partial unfolding of helix α1 (the major structural element of the transmembrane region); this acid-induced destabilization is proposed to prime CLIC1 for membrane insertion by lowering the energy barrier for conversion to the integral membrane form. Equilibrium unfolding studies, fluorescence spectroscopy, CD spectroscopy as a function of pH Biochemistry Medium 18850721
2009 Hydrogen-deuterium exchange mass spectrometry shows that at pH 5.5, domain 1 of CLIC1 (less stable than domain 2) displays enhanced conformational flexibility, particularly in segments 11–31 (including the transmembrane helix α1) and 68–82; acidic pH primes the solution structure by destabilizing domain 1 to lower the activation energy for membrane-insertion conformation. Amide hydrogen-deuterium exchange mass spectrometry (DXMS) at pH 7 and 5.5 Biochemistry Medium 19650640
2012 In resting macrophages CLIC1 resides in cytoplasmic punctate structures; upon phagocytosis of opsonized zymosan, CLIC1 translocates to the phagosomal membrane; CLIC1 knockout macrophages show impaired phagosomal acidification, reduced proteolytic capacity, and reduced ROS production; CLIC1 knockout mice are protected from K/BxN serum-transfer arthritis, establishing CLIC1's role in macrophage phagosomal function via its ion channel activity. Immunofluorescence confocal microscopy, CLIC1 knockout mice, pH-sensitive fluorophore live imaging (Oregon Green-labeled zymosan), flow cytometry for ROS, in vivo arthritis model Journal of cell science High 22956539
2016 CLIC1 in dendritic cells translocates to the phagosomal membrane upon phagocytosis; CLIC1 knockout BMDCs display impaired phagosomal acidification and proteolysis; CLIC1-/- dendritic cells show reduced antigen processing and presentation of full-length MOG protein and reduced MOG-induced experimental autoimmune encephalomyelitis, establishing CLIC1 as a regulator of DC phagosomal pH for optimal antigen processing. CLIC1 knockout mice, bone marrow-derived DC cultures, phagosomal pH measurement, in vitro antigen processing assay, EAE in vivo model, IAA-94 pharmacological blockade Biology open High 27113959
2013 Cholesterol concentration in lipid membranes regulates the spontaneous insertion of CLIC1 and its ion channel conductance; cholesterol-dependent behavior is analogous to cholesterol-dependent-cytolysin family pore-forming proteins; impedance spectroscopy with CLIC1 mutants indicates Cys24 is not essential but important for optimal channel activity. Langmuir lipid monolayer pressure-area measurements, impedance spectroscopy with tethered bilayer membranes, CLIC1 mutants PloS one Medium 23457643
2013 Point mutations in the putative transmembrane region of CLIC1 selectively alter its biophysical properties: K37A alters single-channel conductance while R29A affects single-channel open probability in response to membrane potential; both charged residues directly regulate ion channel activity, confirming CLIC1 itself forms a chloride ion channel. Site-directed mutagenesis (K37A, R29A), single-channel tip-dip bilayer recording, cell-attached and whole-cell patch clamp in transfected HEK cells PloS one High 24058583
2014 CLIC1 ion channel is preferentially active during the G1-S transition in glioblastoma stem cells via transient membrane insertion; metformin inhibits CLIC1-mediated chloride current and induces G1 arrest; mutation of Arg29 in the putative pore region impairs metformin modulation of channel activity, identifying CLIC1 as the direct molecular target of metformin's antiproliferative effect. Perforated patch clamp, siRNA knockdown, R29A mutagenesis, proliferation assays, cell cycle analysis in GBM stem cells Oncotarget High 25361004
2017 Upon LPS stimulation of macrophages, CLIC1 translocates from cytoplasm to nucleus and plasma membrane (confirmed by confocal microscopy and cell fractionation); siRNA knockdown of CLIC1 impairs IL-1β transcription, ASC speck formation, and secretion of mature IL-1β in LPS/ATP-stimulated BMDMs, demonstrating CLIC1 participates both in priming for IL-1β and in NLRP3 inflammasome activation. Confocal microscopy, cell fractionation, siRNA knockdown, ELISA for IL-1β, ASC speck formation assay in BMDMs The Journal of biological chemistry Medium 28576828
2017 CLIC1 null macrophages fail to redistribute NADPH oxidase from an intracellular compartment to the plasma membrane upon PMA stimulation, dramatically decreasing superoxide production; CLIC1 absence does not affect ERM cytoskeleton redistribution or dephosphorylation; CLIC1 knockout mice show attenuated acute tissue injury correlating with absence of ROS rise, establishing CLIC1's role in macrophage superoxide production via NADPH oxidase membrane redistribution. CLIC1 knockout mice, peritoneal macrophage isolation, superoxide assay, immunofluorescence for NADPH oxidase localization, acute tissue injury models Physiological reports High 28275112
2021 CLIC1 recruits PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane in response to migration stimuli; PIP5Ks at the membrane generate a PIP2-rich microdomain that induces integrin-mediated cell-matrix adhesion formation and cytoskeletal extension signaling; CLIC1 silencing inhibits tumor cell attachment, lung alveolar adherence, and extravasation, suppressing lung metastasis in mice. Comparative proteomics, co-immunoprecipitation, live-cell imaging, siRNA knockdown, mouse lung metastasis model, PIP2 immunostaining, integrin adhesion assays The Journal of clinical investigation High 33079727
2021 CLIC1 and CLIC4 transiently translocate to the plasma membrane in response to S1P; CLIC1 (but not CLIC4) is essential for S1P-induced RhoA activation downstream of S1PR2 and S1PR3; both CLIC1 and CLIC4 are required for S1P-induced Rac1 activation downstream of S1PR1; these mechanisms are critical for S1P-induced endothelial barrier function; CLIC1 and CLIC4 are not functionally interchangeable. siRNA knockdown, small GTPase activation assays (Rac1, RhoA), live-cell imaging for CLIC translocation, transendothelial resistance measurement, rescue experiments Science signaling High 33879602
2019 CLIC4 and CLIC1 function together at the cleavage furrow during cytokinesis; CLIC4 accumulates at the cleavage furrow and midbody in a RhoA-dependent manner; CLIC4 interacts with ezrin, anillin, and ALIX at these structures; CLIC4 facilitates ezrin activation at the cleavage furrow; knockout of both CLIC4 and CLIC1 causes abnormal polar cortex blebbing, cleavage furrow regression, and multinucleation. Live-cell imaging, CLIC4/CLIC1 knockout cells, Co-IP (ezrin, anillin, ALIX), site-directed mutagenesis of GST-active residues, ezrin inhibition rescue experiments Life science alliance Medium 31879279
2016 CLIC1 is critical for invadopodium stability in fibrin-embedded cells; membrane-translocated CLIC1 is recruited into invadopodia via β3 integrin (ITGB3)-mediated mechanism; CLIC1 induces stress fiber and fibronectin matrix formation in invadopodia; CLIC1 depletion reduces myosin light chain kinase (MYLK), implicating CLIC1 in integrin-mediated actomyosin dynamics; CLIC1 promotes tumor fibrin colonization and metastasis in vivo. siRNA knockdown, 3D fibrin matrix assays, in vivo metastasis model, SLUG/SNAI2 expression, MYLK measurement, β3 integrin co-depletion Molecular cancer research Medium 25205595
2005 Insulin stimulation of human hematopoietic cells induces subnuclear relocalization of CLIC1 (detected by 2D-electrophoresis proteomics), identifying CLIC1 as a downstream effector of insulin signaling; the relocalization suggests a qualitative/conformational change rather than simple upregulation. 2D-electrophoresis proteomics, 1D Western blot, nuclear localization microscopy, proteasome inhibitor (MG-132) control American journal of physiology. Endocrinology and metabolism Low 15827065
2016 In fluorescence bilayer interaction studies, FRET between CLIC1 Trp35 and a dansyl-labeled lipid analogue under oxidizing conditions reveals CLIC1 associates with membranes at a Trp35-to-dansyl distance of ~15 Å, providing direct structural evidence for oxidation-driven membrane interaction and proposing Trp35 as having a membrane-anchoring role. Fluorescence FRET spectroscopy, fluorescence quenching, dansyl-labeled lipid analogue Biochemistry Medium 27299171
2011 CLT1 peptide binds CLIC1 on angiogenic endothelial cell surfaces; CLT1 forms co-aggregates with fibronectin that are internalized through CLIC1 in a mechanism requiring the LIIQK sequence of CLT1 and integrin αvβ3-mediated translocation of CLIC1 to the cell surface; CLIC1 facilitates internalization of CLT1-fibronectin co-aggregates leading to cytotoxic unfolded protein response. Co-IP/binding assays, live-cell imaging, CLIC1 knockdown, integrin αvβ3 ligation, in vivo tumor model Angiogenesis Medium 22203240
2024 Matrix stiffness elevates CLIC1 expression through Wnt/β-catenin/TCF4 signaling in pancreatic cancer cells; CLIC1 promotes glycolytic (Warburg) metabolism by stabilizing HIF1α through inhibition of hydroxylation via ROS; thus CLIC1 mechanistically links matrix stiffness to the Warburg effect in PDAC. Clinical data integration, in vitro stiffness manipulation, Wnt/β-catenin pathway analysis, HIF1α hydroxylation assay, ROS measurement, siRNA/overexpression experiments Cell reports Medium 39154343

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 The intracellular chloride ion channel protein CLIC1 undergoes a redox-controlled structural transition. The Journal of biological chemistry 191 14613939
2001 Crystal structure of a soluble form of the intracellular chloride ion channel CLIC1 (NCC27) at 1.4-A resolution. The Journal of biological chemistry 173 11551966
1992 Isolation and characterization of two distinct human rotavirus strains with G6 specificity. Journal of clinical microbiology 151 1370851
2017 The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome. The Journal of biological chemistry 142 28576828
2000 The nuclear chloride ion channel NCC27 is involved in regulation of the cell cycle. The Journal of physiology 133 11195932
2014 Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochimica et biophysica acta 124 25546839
2008 CLIC1 function is required for beta-amyloid-induced generation of reactive oxygen species by microglia. The Journal of neuroscience : the official journal of the Society for Neuroscience 118 18987185
2002 The calcium activation of gelsolin: insights from the 3A structure of the G4-G6/actin complex. Journal of molecular biology 115 12460571
2002 CLIC1 inserts from the aqueous phase into phospholipid membranes, where it functions as an anion channel. American journal of physiology. Cell physiology 109 11940526
2004 Involvement of the intracellular ion channel CLIC1 in microglia-mediated beta-amyloid-induced neurotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 107 15190104
2002 Recombinant CLIC1 (NCC27) assembles in lipid bilayers via a pH-dependent two-state process to form chloride ion channels with identical characteristics to those observed in Chinese hamster ovary cells expressing CLIC1. The Journal of biological chemistry 105 11978800
2014 Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current. Oncotarget 104 25361004
2010 Chloride intracellular channel 1 (CLIC1): Sensor and effector during oxidative stress. FEBS letters 104 20385134
2007 Overexpression of CLIC1 in human gastric carcinoma and its clinicopathological significance. Proteomics 94 17154271
2000 Functional characterization of the NCC27 nuclear protein in stable transfected CHO-K1 cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 94 10834939
2007 Functional reconstitution of mammalian 'chloride intracellular channels' CLIC1, CLIC4 and CLIC5 reveals differential regulation by cytoskeletal actin. The FEBS journal 93 18028448
2012 Intracellular chloride channel protein CLIC1 regulates macrophage function through modulation of phagosomal acidification. Journal of cell science 90 22956539
2005 Redox regulation of CLIC1 by cysteine residues associated with the putative channel pore. Biophysical journal 89 16339885
2015 Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth. Oncotarget 79 26429879
2013 Functional role of CLIC1 ion channel in glioblastoma-derived stem/progenitor cells. Journal of the National Cancer Institute 79 24115360
2000 CLIC-1 functions as a chloride channel when expressed and purified from bacteria. The Journal of biological chemistry 79 10874038
2008 Expression of chloride intracellular channel protein 1 (CLIC1) and tumor protein D52 (TPD52) as potential biomarkers for colorectal cancer. Clinical biochemistry 78 18710659
2013 Evidence that the Echinococcus granulosus G6 genotype has an affinity for the brain in humans. International journal for parasitology 76 23891711
2018 Molecular phylogeny based on six nuclear genes suggests that Echinococcus granulosus sensu lato genotypes G6/G7 and G8/G10 can be regarded as two distinct species. Parasitology 74 29781421
1998 Mitochondrial genomic markers confirm the presence of the camel strain (G6 genotype) of Echinococcus granulosus in north-western China. Parasitology 73 9481771
2017 Tanshinone IIA Sodium sulfonate regulates antioxidant system, inflammation, and endothelial dysfunction in atherosclerosis by downregulation of CLIC1. European journal of pharmacology 67 28970012
2009 Cell secretome analysis using hollow fiber culture system leads to the discovery of CLIC1 protein as a novel plasma marker for nasopharyngeal carcinoma. Journal of proteome research 63 19845400
2004 Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-beta1. Journal of leukocyte biology 61 15459235
2005 Molecular evidence of ovine (G1) and camel (G6) strains of Echinococcus granulosus in Tunisia and putative role of cattle in human contamination. Veterinary parasitology 59 15845282
2003 Genetic variability among serotype G6 human rotaviruses: identification of a novel lineage isolated in Hungary. Journal of medical virology 59 12858418
2021 CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis. The Journal of clinical investigation 58 33079727
2007 Tissue and subcellular distribution of CLIC1. BMC cell biology 57 17326840
1995 Genetic and antigenic characterization of a serotype G6 human rotavirus isolated in Melbourne, Australia. Journal of medical virology 55 8636702
2012 Regulation of colon cancer cell migration and invasion by CLIC1-mediated RVD. Molecular and cellular biochemistry 52 22426742
2001 Characterisation and phylogenetic analysis of the VP7 proteins of serotype G6 and G8 human rotaviruses. Journal of medical microbiology 52 11339255
2010 Molecular characterization of Echinococcus isolates indicates goats as reservoir for Echinococcus canadensis G6 genotype in Neuquén, Patagonia Argentina. Parasitology international 51 20667482
2003 Antisense suppression of a beta-galactosidase gene (TB G6) in tomato increases fruit cracking. Journal of experimental botany 50 12867545
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2017 Genetic differentiation of the G6/7 cluster of Echinococcus canadensis based on mitochondrial marker genes. International journal for parasitology 40 28780151
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2005 The soluble pool of HLA-G produced by human trophoblasts does not include detectable levels of the intron 4-containing HLA-G5 and HLA-G6 isoforms. Molecular human reproduction 40 16330474
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2013 Antigenic differences between the EG95-related proteins from Echinococcus granulosus G1 and G6 genotypes: implications for vaccination. Parasite immunology 37 23009356
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2011 The expression and clinical significance of CLIC1 and HSP27 in lung adenocarcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36 21858536
2005 Proteomic analysis on insulin signaling in human hematopoietic cells: identification of CLIC1 and SRp20 as novel downstream effectors of insulin. American journal of physiology. Endocrinology and metabolism 36 15827065
2018 Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability. Frontiers in pharmacology 35 30186163
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