Affinage

CLIC4

Chloride intracellular channel protein 4 · UniProt Q9Y696

Length
253 aa
Mass
28.8 kDa
Annotated
2026-04-28
100 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLIC4 is a redox-sensitive, metamorphic protein that functions as a soluble cytosolic GST-fold protein capable of autoinserting into lipid bilayers to form poorly selective, low-conductance ion channels regulated by trans-membrane redox potential (PMID:17453412, PMID:12237120). In response to G13/RhoA-coupled receptor signaling, CLIC4 translocates to discrete plasma membrane domains in an F-actin- and Cys35-dependent manner (PMID:19776349), while S-nitrosylation at Cys35 triggers conformational unfolding, association with importin-α/Ran, and nuclear translocation, where CLIC4 protects phospho-Smad2/3 from dephosphorylation to sustain TGF-β signaling and growth arrest (PMID:20504765, PMID:19448624, PMID:22613027). CLIC4 regulates vesicular trafficking—controlling β1 integrin recycling via Rab35 suppression (PMID:25344254), BMPRII lysosomal targeting through Arf6 (PMID:30582444), and retromer-mediated apical transport during tubulogenesis (PMID:26786190)—and participates in cytokinesis by bridging the plasma membrane to cortical actin through ezrin at the cleavage furrow (PMID:31879279). CLIC4 also modulates innate immunity by promoting IRF3 phosphorylation and NLRP3 inflammasome activation in macrophages (PMID:21469130, PMID:28576828), and localizes to mitochondrial-associated membranes where it maintains ER–mitochondrial calcium homeostasis to confer cardioprotection against ischemia-reperfusion injury (PMID:36269835).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 Medium

    The initial characterization established that CLIC4 (p64H1) localizes to the endoplasmic reticulum and can reconstitute anion channel activity from ER vesicles, establishing it as a candidate intracellular chloride channel subject to PKC-mediated phosphorylation.

    Evidence In vitro expression in HEK293 cells with immunolocalization and planar lipid bilayer reconstitution of ER vesicles

    PMID:9295337

    Open questions at the time
    • Channel activity was from ER vesicles, not purified protein, so contribution of other ER proteins could not be excluded
    • Functional consequence of PKC phosphorylation on channel gating was not determined
  2. 1999 Medium

    Subcellular mapping in neurons revealed CLIC4 specifically associates with large dense-core vesicles and microtubules rather than small synaptic vesicles, suggesting a role in acidification of secretory granules distinct from a general ER channel function.

    Evidence Immunoelectron microscopy and subcellular fractionation in rat hippocampal neurons

    PMID:10191309

    Open questions at the time
    • No direct measurement of vesicular pH or chloride flux was performed
    • Functional relevance to LDCV maturation or neuropeptide processing not tested
  3. 2002 Medium

    Patch-clamp electrophysiology in intact cells demonstrated that CLIC4 overexpression generates novel plasma membrane anion channels with cytoplasmic C-terminal topology, establishing that CLIC4 itself is an essential component of a cellular ion channel rather than a channel regulator.

    Evidence Stable transfection in HEK-293 cells, patch-clamp recording, antibody inhibition from cytoplasmic versus external face

    PMID:12237120

    Open questions at the time
    • Overexpression system may not reflect endogenous channel density or selectivity
    • Identity of any accessory subunits was not addressed
  4. 2003 High

    Discovery that stress stimuli drive CLIC4 nuclear translocation via an NLS-dependent, importin-α/Ran-mediated pathway, and that nuclear-targeted CLIC4 accelerates apoptosis independently of Apaf-1 and Bcl-2, revealed a non-channel, nuclear effector role for CLIC4.

    Evidence Immunogold EM, confocal microscopy, co-IP, adenoviral nuclear targeting, NLS mutation, Apaf-null and Bcl-2-overexpressing cells

    PMID:14610078

    Open questions at the time
    • Nuclear target or mechanism by which CLIC4 promotes apoptosis was not identified
    • Physiological stress-relevant stimuli driving translocation in vivo were not defined
  5. 2005 High

    Functional knockdown experiments showed CLIC4 is required for endothelial tubular morphogenesis, linking CLIC4 to tissue-level lumen formation and angiogenesis beyond ion channel activity.

    Evidence siRNA and antisense suppression in endothelial tubulogenesis assays with confocal imaging

    PMID:16239224

    Open questions at the time
    • Whether lumen formation defect is due to ion channel activity, vesicle trafficking, or another function was not resolved
    • In vivo angiogenesis phenotype was not tested
  6. 2007 High

    Reconstitution of purified CLIC4 into planar lipid bilayers definitively showed it forms poorly selective ~15 pS channels regulated by trans-redox potential, with the N-terminal transmembrane domain (residues 1–61) sufficient for pore formation, resolving the long-standing question of whether CLIC4 is a bona fide channel-forming protein.

    Evidence Planar lipid bilayer reconstitution with purified recombinant full-length and truncated protein, redox manipulation

    PMID:17453412 PMID:18028448

    Open questions at the time
    • Channel selectivity is poor, questioning whether chloride conduction is the primary physiological function
    • No in vivo evidence that ion channel activity accounts for CLIC4 cellular phenotypes
  7. 2009 High

    Two independent studies established the two major stimulus-dependent trafficking pathways: G13/RhoA-coupled receptor activation drives rapid CLIC4 translocation to discrete plasma membrane domains in an actin- and Cys35-dependent manner, while TGF-β drives CLIC4/Schnurri-2 nuclear co-translocation where CLIC4 protects phospho-Smad2/3 from dephosphorylation to sustain signaling.

    Evidence Live-cell imaging with dominant-negative/constitutively active RhoA, mutagenesis (C35A), pharmacological inhibitors; co-IP, siRNA, nuclear-targeting constructs, phospho-Smad reporter assays

    PMID:19448624 PMID:19776349

    Open questions at the time
    • The structural basis for how CLIC4 shields phospho-Smads from phosphatases was not determined
    • Whether membrane translocation and nuclear translocation are mutually exclusive fates was not tested
  8. 2010 High

    The molecular trigger for nuclear translocation was identified as S-nitrosylation at Cys35, which induces conformational unfolding and enhances importin-α/Ran binding, providing a redox-sensing mechanism linking NO signaling to CLIC4 nuclear function.

    Evidence Biotin switch assay, CD spectroscopy, trypsinolysis, co-IP with importin-α/Ran, cysteine mutagenesis, NOS inhibition

    PMID:20504765

    Open questions at the time
    • Whether S-nitrosylation and membrane insertion are competing fates for the same Cys35 was not directly tested
    • Crystal structure of the S-nitrosylated form was not obtained
  9. 2011 High

    CLIC4-null mice showed protection from LPS lethality with impaired IRF3 phosphorylation but intact NF-κB and MAPK signaling, establishing CLIC4 as a selective regulator of the innate immune TLR4–IRF3 axis in macrophages.

    Evidence CLIC4-null mouse LPS lethality and Listeria infection models, phospho-IRF3 Western blot, CLIC4 overexpression

    PMID:21469130

    Open questions at the time
    • Direct physical mechanism by which CLIC4 promotes IRF3 phosphorylation was not identified
    • Whether this is a channel-dependent or scaffolding function was not resolved
  10. 2012 High

    In vivo validation in CLIC4-null mice confirmed that CLIC4 is required for TGF-β-dependent wound healing: null keratinocytes show reduced phospho-Smad2 and impaired migration, and nuclear CLIC4 reconstitution in squamous cancer cells restores TGF-β-dependent growth suppression, integrating the NO/S-nitrosylation pathway with TGF-β signaling and tumor suppression.

    Evidence CLIC4-null mouse wound healing assays, keratinocyte migration/adhesion assays, adenoviral nuclear targeting in squamous cancer orthografts, biotin switch

    PMID:22387366 PMID:22613027

    Open questions at the time
    • Whether loss of nuclear CLIC4 is a cause or consequence of squamous carcinogenesis was not fully resolved
    • The phosphatase(s) counteracted by nuclear CLIC4 were not identified
  11. 2014 High

    The discovery that CLIC4 regulates β1 integrin trafficking by suppressing Rab35 activity at endosomes, controlling both internalization and LPA-stimulated recycling, established CLIC4 as a GTPase regulator in the endosomal compartment with direct consequences for cell adhesion and motility.

    Evidence siRNA knockdown, confocal co-localization, integrin recycling/internalization assays, Rab35 activity assay, cell adhesion and motility assays

    PMID:25344254

    Open questions at the time
    • Biochemical mechanism by which CLIC4 suppresses Rab35 (GAP activation or direct inhibition) was not determined
    • Whether channel activity contributes to endosomal trafficking function is unknown
  12. 2016 High

    CLIC4-null mice confirmed a requirement for CLIC4 in renal tubulogenesis in vivo, and 3D culture studies revealed that CLIC4 controls retromer-mediated apical transport by negatively regulating branched actin on early endosomes, with Rab8 and Cdc42 epistatic rescue, placing CLIC4 upstream of apical polarity establishment.

    Evidence CLIC4-null mouse kidneys, MDCK 3D culture, live imaging, Rab8/Cdc42 rescue, subcellular fractionation

    PMID:26786190

    Open questions at the time
    • Molecular mechanism of actin regulation on endosomes (direct or via an intermediate effector) was not identified
    • Relationship between Rab35 suppression and retromer regulation was not clarified
  13. 2017 High

    CLIC4 was shown to be required for both NLRP3 inflammasome priming (IL-1β transcription) and activation (ASC speck formation and mature IL-1β secretion), broadening its innate immune role beyond IRF3 to include inflammasome assembly.

    Evidence siRNA knockdown in macrophages, confocal imaging, cell fractionation, IL-1β transcription and ELISA

    PMID:28576828

    Open questions at the time
    • Whether CLIC4 acts through ion channel activity, scaffolding, or a signaling pathway at the inflammasome was not resolved
    • Direct physical association with NLRP3 or ASC was not shown
  14. 2019 High

    Two studies revealed new CLIC4 functions: at the cleavage furrow, CLIC4 is recruited in a RhoA/Cys35-dependent manner, interacts with ezrin to bridge membrane and actin during cytokinesis (CLIC4/CLIC1 double knockout causes multinucleation); and in endothelial cells, CLIC4 acts through Arf6 to regulate gyrating clathrin and BMPRII lysosomal targeting, with implications for pulmonary hypertension.

    Evidence Live-cell imaging, CLIC4/CLIC1 knockout, co-IP, mutagenesis (C35A, F37D), ezrin inhibition; proteomic interactome, Arf6 siRNA epistasis, in vivo pulmonary hypertension model

    PMID:30582444 PMID:31879279

    Open questions at the time
    • Structural basis for CLIC4–ezrin interaction and its dependence on the GST fold is unknown
    • Whether Arf6-mediated and Rab35-mediated trafficking roles are part of a unified mechanism is not established
  15. 2022 High

    CLIC4 was localized to mitochondrial-associated membranes (MAMs) in cardiomyocytes, and CLIC4-null mice exhibited increased ischemia-reperfusion injury with disrupted ER–mitochondrial calcium homeostasis, establishing a cardioprotective role through inter-organellar calcium regulation.

    Evidence MAM fractionation, CLIC4-null mouse cardiac ischemia-reperfusion model, calcium imaging, mitochondrial function assays

    PMID:36269835

    Open questions at the time
    • Whether CLIC4 ion channel activity at MAMs mediates calcium transfer or whether it acts as a scaffolding protein is not resolved
    • Direct binding partners at MAMs (e.g. IP3R, VDAC, MFN2) were not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The central unresolved question is how CLIC4's multiple molecular activities — ion channel formation, GTPase regulation (Rab35, Arf6), phospho-Smad protection, and ezrin activation — are coordinated and whether they depend on a common structural switch (soluble GST-fold vs. membrane-inserted form) or represent independent functions of distinct CLIC4 pools.
  • No high-resolution structure of membrane-inserted CLIC4 exists
  • Separation-of-function mutants distinguishing channel vs. scaffolding vs. enzymatic roles have not been generated
  • The relationship between redox-dependent conformational change and specific cellular outcomes remains unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 5 GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2 GO:0005768 endosome 2 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-168256 Immune System 2 R-HSA-1640170 Cell Cycle 1
Partners
ARF6EZRKPNA1RAB35RHOASHN2SMAD2SMAD3

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CLIC4 localizes to mitochondria and cytoplasm of keratinocytes and translocates to the nucleus in response to multiple stress inducers. Nuclear CLIC4 is detected prior to the apoptotic phenotype, associates with Ran, NTF2, and Importin-α nuclear import complexes, requires an intact C-terminal nuclear localization signal for translocation, and nuclear-targeted CLIC4 accelerates apoptosis independently of Apaf-1 and Bcl-2. Immunogold electron microscopy, confocal microscopy, co-immunoprecipitation, adenoviral nuclear targeting, deletion/mutation of NLS, Apaf-null and Bcl-2-overexpressing cell lines The Journal of biological chemistry High 14610078
2009 TGF-β promotes expression of CLIC4 and Schnurri-2, their cytoplasmic association, and co-translocation to the nucleus. In the nucleus, CLIC4 associates with phospho-Smad2 and phospho-Smad3, protecting them from dephosphorylation by nuclear phosphatases, thereby sustaining TGF-β signaling and enabling growth arrest. Co-immunoprecipitation, nuclear targeting adenoviral constructs, siRNA knockdown, phospho-Smad reporter assays, genetic epistasis (Schnurri-2 and CLIC4 siRNA) Nature cell biology High 19448624
2010 CLIC4 undergoes S-nitrosylation at a cysteine residue in response to NO or TNF-α (via nitric oxide synthase). S-nitrosylation induces a conformational change (protein unfolding), enhances CLIC4 association with importin-α and Ran, and drives nuclear translocation independently of the NO-cGMP pathway. Cysteine mutants show altered nitrosylation, nuclear residence, and stability. Biotin switch assay, CD spectra analysis, trypsinolysis, co-immunoprecipitation with importin-α and Ran, cysteine mutagenesis, NOS inhibition, confocal imaging The Journal of biological chemistry High 20504765
2009 Cytosolic CLIC4 undergoes rapid but transient translocation to discrete plasma membrane domains upon activation of G13-coupled, RhoA-activating receptors (LPA, thrombin, sphingosine-1-phosphate). Translocation is strictly dependent on Gα13-mediated RhoA activation and F-actin integrity but not Rho kinase activity, and requires at least six conserved residues including reactive Cys35 (equivalent to the catalytic cysteine of GSTs). Live-cell imaging, dominant-negative and constitutively active RhoA constructs, pharmacological inhibitors, site-directed mutagenesis, chloride current measurements Molecular biology of the cell High 19776349
2007 Recombinant CLIC4 autoinserts into planar lipid bilayers to form ion channels with maximum conductance ~15 pS in KCl. The channels are poorly selective between anions and cations, and their conductance is regulated by trans (luminal/external) redox potential. A truncated N-terminal fragment containing the predicted transmembrane domain (residues 1–61) also forms non-selective channels with retained trans-redox sensitivity, identifying the TMD as an essential pore component. Planar lipid bilayer reconstitution, recombinant protein expression, truncation constructs, redox manipulation with DTNB Molecular membrane biology High 17453412
2007 Purified recombinant CLIC4 incorporated into planar lipid bilayers forms ion channels. Unlike CLIC1 and CLIC5, CLIC4 channels are not inhibited by cytoskeletal F-actin, revealing differential regulation of CLIC family members by actin. Planar lipid bilayer reconstitution with purified recombinant protein, cytochalasin treatment to disrupt F-actin The FEBS journal High 18028448
2005 CLIC4 expression decreases during VEGF-induced endothelial cell tubular morphogenesis. Subcellular localization of CLIC4 shifts depending on whether endothelial cells are proliferating or forming tubes. Antisense- and siRNA-mediated suppression of CLIC4 arrests tubular morphogenesis, implicating CLIC4 in lumen formation. 2D proteomics, siRNA knockdown, antisense suppression, confocal microscopy of subcellular localization, in vitro tubulogenesis assay The Journal of biological chemistry High 16239224
2014 CLIC4 regulates β1 integrin trafficking: it is required for both internalization and LPA/serum-induced recycling of β1 integrin (but not EGFR). CLIC4 is recruited to β1 integrin at the plasma membrane and in Rab35-positive endosomes upon LPA stimulation. CLIC4 suppresses Rab35 activity, and CLIC4 knockdown decreases cell-matrix adhesion, cell spreading, and integrin signaling while increasing cell motility. siRNA knockdown, co-localization confocal imaging, integrin recycling/internalization assays, Rab35 activity assay, cell adhesion and motility assays Journal of cell science High 25344254
2016 CLIC4-null mice exhibit impaired renal tubulogenesis. In MDCK 3D cultures, CLIC4 localizes to early endosomes, recycling endosomes, and apical transport carriers before reaching steady-state apical membrane localization. CLIC4 suppression impairs apical vesicle coalescence and central lumen formation, rescued by Rab8 and Cdc42. CLIC4 selectively modulates retromer-mediated apical transport by negatively regulating branched actin formation on early endosomes. CLIC4-null mouse kidney analysis, MDCK 3D culture, siRNA knockdown, live imaging, Rab8 and Cdc42 rescue experiments, subcellular fractionation Nature communications High 26786190
2019 CLIC4 accumulates at the cleavage furrow and midbody at cytokinesis onset in a RhoA-dependent manner. This cell-cycle-dependent localization requires GST activity-related residues C35 and F37. CLIC4 interacts with ezrin, anillin, and ALIX at these structures; facilitates ezrin activation at the cleavage furrow; and reciprocally depends on ezrin activation for its own recruitment. CLIC4 and CLIC1 double knockout causes polar cortex blebbing and cleavage furrow regression, resulting in multinucleated cells. Live-cell imaging, CLIC4/CLIC1 knockout, co-immunoprecipitation, site-directed mutagenesis (C35A, F37D), ezrin inhibition, cytokinesis phenotype quantification Life science alliance High 31879279
2019 CLIC4 interacts with Arf6 GTPase-activating proteins and clathrin (identified by proteomics). CLIC4 overexpression reduces BMPRII expression and signaling through Arf6-mediated reduction of gyrating clathrin and increased lysosomal targeting of the receptor. CLIC4 effects on NF-κB, HIF, and angiogenic response are prevented by Arf6 siRNA, establishing Arf6 as a downstream effector of CLIC4. Proteomic interactome analysis, co-immunoprecipitation, siRNA knockdown of Arf6, pharmacological inhibitors of clathrin-mediated endocytosis and Arf, BMPRII expression/signaling assays, in vivo pulmonary hypertension models Circulation research High 30582444
2017 CLIC1 and CLIC4 translocate to the nucleus and cellular membrane upon LPS stimulation of macrophages (by confocal microscopy and cell fractionation). siRNA knockdown of CLIC4 impairs IL-1β transcription, ASC speck formation, and secretion of mature IL-1β in LPS/ATP-stimulated macrophages, demonstrating roles in both NLRP3 inflammasome priming and activation. Confocal microscopy, cell fractionation, siRNA knockdown, IL-1β transcription measurement, ASC speck formation assay, ELISA for mature IL-1β The Journal of biological chemistry High 28576828
2011 CLIC4-null mice are protected from LPS-induced death with reduced serum inflammatory cytokines. CLIC4 deficiency impairs clearance of Listeria monocytogenes and reduces cytokine/chemokine production. Mechanistically, CLIC4 deletion reduces accumulation of phosphorylated IRF3 in macrophages upon LPS stimulation, while CLIC4 overexpression enhances LPS-mediated IRF3 phosphorylation, without affecting MAPK or NF-κB activation. CLIC4-null mouse generation, LPS lethality model, Listeria infection model, Western blot for phospho-IRF3, MAPK and NF-κB activation assays, stable overexpression cell lines European journal of immunology High 21469130
2012 CLIC4 is S-nitrosylated and translocates to the nucleus in metabolically stressed keratinocytes, where it enhances TGF-β signaling by protecting phospho-Smad2/3 from dephosphorylation. Loss of nuclear CLIC4 in squamous cancer cells is associated with altered redox state. Adenoviral reconstitution of nuclear CLIC4 in squamous cancer cells enhances TGF-β-dependent transcription and inhibits growth in vitro and in orthograft models. Biotin switch assay, adenoviral nuclear targeting, TGF-β transcriptional reporter, orthograft tumor models, transgenic mouse epidermis, CLIC4-null keratinocyte Smad phosphorylation assay Carcinogenesis High 22387366
2012 CLIC4-null mice develop spontaneous skin erosions after 6 months and show delayed wound reepithelialization and impaired corneal wound healing. CLIC4-null keratinocytes show reduced TGF-β-induced phospho-Smad2, slower migration, failure to increase migration in response to TGF-β, and reduced adhesion, linking CLIC4 to TGF-β pathway function in epithelial wound healing. CLIC4 genetic knockout mouse, full-thickness skin and corneal wound healing assays, phospho-Smad2 Western blot, keratinocyte migration and adhesion assays The American journal of pathology High 22613027
2002 Overexpression of CLIC4 in HEK-293 cells generates plasma membrane anion channels sensitive to indanyloxyacetic acid (IC50 ~100 µM) with low conductance (~1 pS), inhibited by anti-CLIC4 antibodies applied to the cytoplasmic face only, demonstrating CLIC4 is an essential molecular component of novel cellular anion channels with a cytoplasmic C-terminus in the membrane form. Stable transfection, patch-clamp electrophysiology, antibody inhibition from cytoplasmic vs. external face Biochemical and biophysical research communications Medium 12237120
1997 Rat brain p64H1 (CLIC4 ortholog) expressed in HEK293 cells localizes to the endoplasmic reticulum by immunofluorescence. Incorporation of HEK293 ER vesicles into planar lipid bilayers reconstitutes intermediate conductance, outwardly rectifying anion channels. Protein kinase C-mediated phosphorylation increases the apparent molecular weight of p64H1 from ~29 kDa to ~43 kDa. In vitro expression, immunolocalization, planar lipid bilayer reconstitution of ER vesicles, PKC phosphorylation assay The Journal of biological chemistry Medium 9295337
1999 p64H1 (CLIC4) in rat hippocampal neurons is specifically associated with large dense-core vesicles (LDCVs) and microtubules by immunoelectron microscopy, with very low labeling in perikarya or small synaptic vesicles, suggesting a role in maintaining low internal pH of LDCVs and LDCV maturation. Immunoelectron microscopy, subcellular fractionation, immunoblot of membrane fractions The Journal of neuroscience Medium 10191309
2022 CLIC4 is present in mitochondrial-associated membranes (MAMs) of cardiomyocytes. CLIC4-null mice show increased myocardial infarction and reduced cardiac function after ischemia-reperfusion injury. CLIC4-null cardiomyocytes exhibit increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation, and altered ER and mitochondrial calcium homeostasis. Subcellular fractionation (MAM isolation), CLIC4-null mouse cardiac ischemia-reperfusion model, calcium imaging, mitochondrial function assays, cardiomyocyte hypoxia-reoxygenation model Science advances High 36269835
2015 Clic4 sensitizes pancreatic β-cells to cytokine-induced apoptosis by reducing the steady-state levels of Bcl-2, Bad, and phosphorylated Bad. Clic4 co-purifies with proteasome components by co-immunoprecipitation and mass spectrometry, suggesting it regulates Bcl-2 family protein stability via the proteasome. β-cell-specific Clic4 knockout mice and siRNA-silenced cells show reduced cytokine-induced apoptosis. β-cell-specific Clic4 knockout mice, siRNA silencing, co-immunoprecipitation/mass spectrometry, protein half-life measurements, Bcl-2/Bad Western blot Molecular metabolism Medium 25830089
2022 FTO-mediated m6A demethylation stabilizes CLIC4 mRNA; FTO depletion increases m6A modification on CLIC4 mRNA and reduces its stability, leading to decreased CLIC4 expression and increased prostate cancer proliferation and metastasis. MeRIP-RT-qPCR, RNA-sequencing, mRNA stability assays, siRNA knockdown, overexpression studies, in vitro and in vivo tumor models Cell death discovery Medium 35397614
2021 miR-135a-5p directly binds the 3′-UTR of CLIC4 mRNA (validated by dual-luciferase reporter and RNA pull-down assay), suppressing CLIC4 expression. The circ_0000231/miR-135a-5p/CLIC4 axis mediates oxidized LDL-induced HUVEC injury in an atherosclerosis cell model. Dual-luciferase reporter assay, RNA pull-down assay, qRT-PCR, Western blot, gain/loss-of-function experiments Molecular and cellular biochemistry Medium 33439448

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 430 18223165
2000 Rapid exchange of histone H1.1 on chromatin in living human cells. Nature 332 11130728
2014 Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature 328 24463520
1986 Roles of H1 domains in determining higher order chromatin structure and H1 location. Journal of molecular biology 288 3458926
1975 Chemical differentiation of histamine H1- and H2-receptor agonists. Journal of medicinal chemistry 287 240025
2016 Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone. Seminars in cell & developmental biology 193 27838364
2005 The dynamics of histone H1 function in chromatin. Molecular cell 183 15749012
2006 Loss of linker histone H1 in cellular senescence. The Journal of cell biology 178 17158953
2013 H1 histones: current perspectives and challenges. Nucleic acids research 173 23945933
2001 Origin of H1 linker histones. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 169 11149891
1999 Histone H1: location and role. Current opinion in cell biology 166 10395563
1995 Mice develop normally without the H1(0) linker histone. Proceedings of the National Academy of Sciences of the United States of America 149 7604008
1987 Microheterogeneity in H1 histones and its consequences. International journal of peptide and protein research 148 3323091
2016 The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science (New York, N.Y.) 144 27708074
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
1999 Properties of cloned and expressed human RNase H1. The Journal of biological chemistry 142 10497183
2003 The organellular chloride channel protein CLIC4/mtCLIC translocates to the nucleus in response to cellular stress and accelerates apoptosis. The Journal of biological chemistry 128 14610078
1975 Histamine H1- and H2-receptors in pulmonary and systemic vasculature of the dog. The American journal of physiology 127 242221
1997 Rat brain p64H1, expression of a new member of the p64 chloride channel protein family in endoplasmic reticulum. The Journal of biological chemistry 107 9295337
2007 Functional reconstitution of mammalian 'chloride intracellular channels' CLIC1, CLIC4 and CLIC5 reveals differential regulation by cytoskeletal actin. The FEBS journal 93 18028448
2017 Histone HIST1H1C/H1.2 regulates autophagy in the development of diabetic retinopathy. Autophagy 89 28409999
2014 PTEN interacts with histone H1 and controls chromatin condensation. Cell reports 88 25199838
2005 Proteomic analysis of vascular endothelial growth factor-induced endothelial cell differentiation reveals a role for chloride intracellular channel 4 (CLIC4) in tubular morphogenesis. The Journal of biological chemistry 87 16239224
2009 TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3. Nature cell biology 86 19448624
1977 Histamine H1- and H2-receptor vasodilation of canine intestinal circulation. The American journal of physiology 86 910911
2007 CLIC4 (p64H1) and its putative transmembrane domain form poorly selective, redox-regulated ion channels. Molecular membrane biology 76 17453412
1999 A 29 kDa intracellular chloride channel p64H1 is associated with large dense-core vesicles in rat hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 74 10191309
2007 Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 73 17200346
2000 Antiallergic effects of H1-receptor antagonists. Allergy 72 11291777
1991 Comparative safety of H1 antihistamines. Annals of allergy 72 1684274
2004 Histone H1 and the origin of protamines. Proceedings of the National Academy of Sciences of the United States of America 71 15024099
1983 Phosphorylation of H1 histones. Molecular and cellular biochemistry 71 6358859
2018 Destabilization of linker histone H1.2 is essential for ATM activation and DNA damage repair. Cell research 70 29844578
1999 H1-receptor antagonists: safety issues. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 68 10582735
1999 Evidence for interaction between human PRUNE and nm23-H1 NDPKinase. Oncogene 68 10602478
1997 Histone H1. The international journal of biochemistry & cell biology 62 9570139
1981 Conformation studies of histone H1(0) in comparison with histones H1 and H5. European journal of biochemistry 58 7318833
1997 Down-regulation of the nm23.h1 gene inhibits cell proliferation. International journal of cancer 53 9335458
1980 Evidence for both histamine H1- and H2-receptors in the gastric vasculature of the cat. British journal of pharmacology 52 6445766
2016 Photoperiod-H1 (Ppd-H1) Controls Leaf Size. Plant physiology 51 27457126
2014 CLIC4 regulates cell adhesion and β1 integrin trafficking. Journal of cell science 51 25344254
2000 Rapid dephosphorylation of H1 histones after apoptosis induction. The Journal of biological chemistry 51 10874037
2003 The histone-like protein H1-S and the response of tomato leaves to water deficit. Journal of experimental botany 50 14645393
2018 Histamine H1 Receptor Contributes to Vestibular Compensation. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 30413645
2005 CLIC4, an intracellular chloride channel protein, is a novel molecular target for cancer therapy. The journal of investigative dermatology. Symposium proceedings 49 16358817
1997 Characterization of the H1.5 gene completes the set of human H1 subtype genes. Gene 48 9031620
2019 CLIC4/Arf6 Pathway. Circulation research 47 30582444
2011 Role of CLIC4 in the host innate responses to bacterial lipopolysaccharide. European journal of immunology 46 21469130
2009 Spatiotemporal regulation of chloride intracellular channel protein CLIC4 by RhoA. Molecular biology of the cell 46 19776349
2015 Linker histone H1.2 establishes chromatin compaction and gene silencing through recognition of H3K27me3. Scientific reports 45 26581166
2012 CLIC4 is a tumor suppressor for cutaneous squamous cell cancer. Carcinogenesis 41 22387366
2006 Nm23-H1: a metastasis-associated gene. Taiwanese journal of obstetrics & gynecology 41 17197349
2001 Skin concentrations of H1-receptor antagonists. The Journal of allergy and clinical immunology 41 11240955
2016 CLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer- and actin-mediated endocytic trafficking. Nature communications 40 26786190
2012 Functional interplay between p53 acetylation and H1.2 phosphorylation in p53-regulated transcription. Oncogene 40 22249259
2009 Molecular dynamics of histone H1. Biochemistry and cell biology = Biochimie et biologie cellulaire 40 19234534
2022 N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability. Cell death discovery 38 35397614
2010 S-nitrosylation regulates nuclear translocation of chloride intracellular channel protein CLIC4. The Journal of biological chemistry 38 20504765
2005 Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 38 16273334
2017 Huwe1 Sustains Normal Ovarian Epithelial Cell Transformation and Tumor Growth through the Histone H1.3-H19 Cascade. Cancer research 37 28687618
2013 Alterations of histone H1 phosphorylation during bladder carcinogenesis. Journal of proteome research 37 23675690
2018 CLIC1 and CLIC4 complement CA125 as a diagnostic biomarker panel for all subtypes of epithelial ovarian cancer. Scientific reports 36 30282979
2022 CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection. Science advances 35 36269835
2018 The Roles of E93 and Kr-h1 in Metamorphosis of Nilaparvata lugens. Frontiers in physiology 35 30524315
2007 CLIC4, skin homeostasis and cutaneous cancer: surprising connections. Molecular carcinogenesis 34 17443730
1999 Non-H1-receptor effects of antihistamines. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 33 10444211
2021 Astragaloside IV alleviates atherosclerosis through targeting circ_0000231/miR-135a-5p/CLIC4 axis in AS cell model in vitro. Molecular and cellular biochemistry 32 33439448
2016 Knockdown of CLIC4 enhances ATP-induced HN4 cell apoptosis through mitochondrial and endoplasmic reticulum pathways. Cell & bioscience 31 26816615
2015 Interplay between histone H1 structure and function. Biochimica et biophysica acta 31 26415976
2012 Ophthalmic antihistamines and H1-H4 receptors. Current opinion in allergy and clinical immunology 31 22918191
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