CLIC4 Gene

HGNC Family	Ion channels
Name	chloride intracellular channel 4
Description	Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 4 (CLIC4) protein, encoded by the CLIC4 gene, is a member of the p64 family; the gene is expressed in many tissues and exhibits a intracellular vesicular pattern in Panc-1 cells (pancreatic cancer cells). [provided by RefSeq, Jul 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Chloride intracellular channel 4 (CLIC4) is a multifunctional protein whose activity and subcellular localization are dynamically regulated in response to diverse cellular stresses, contributing to several key biological processes. Under conditions such as DNA damage or p53 activation, CLIC4 levels increase in mitochondria where its overexpression induces a loss of mitochondrial membrane potential, cytochrome c release, caspase activation, and ultimately apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In stress‐challenged keratinocytes, cytoplasmic CLIC4 translocates to the nucleus via its interaction with nuclear import complexes; this nuclear trafficking accelerates the apoptotic response by initiating nuclear alterations independent of some classical apoptotic regulators."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in apoptosis, CLIC4 is implicated in modulating innate immune responses. It participates in the activation of the NLRP3 inflammasome by mediating chloride efflux downstream of mitochondrial reactive oxygen species production, a process necessary for NEK7–NLRP3 interaction and subsequent IL‐1β maturation and secretion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n CLIC4 also plays a crucial part in vascular biology. It is required for proper endothelial tubulogenesis, as its normal expression supports endothelial cell proliferation, capillary network formation, sprouting, and lumen formation; conversely, reduced CLIC4 expression impairs these angiogenic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, CLIC4 enhances transforming growth factor–β (TGF‑β) signaling by translocating to the nucleus where it associates with phosphorylated Smad2/3, protecting them from dephosphorylation. This stabilization of p‐Smads augments TGF‑β–mediated growth arrest."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the tumor microenvironment, CLIC4 exerts a dual influence. Its up‐regulation in fibroblasts is required for TGF‑β–induced fibroblast‐to‐myofibroblast conversion—a process associated with reactive oxygen species that contributes to stromal remodeling and, ultimately, tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Conversely, loss of CLIC4 in tumor epithelial cells, coupled with over‐expression in stromal/myofibroblast compartments, has been correlated with malignant progression and poor clinical outcome, highlighting its potential as a diagnostic marker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, CLIC4 interacts with cytoskeletal and scaffolding proteins at the centrosome, midbody, and cell cortex, suggesting roles in cytoskeletal organization, regulation of cell division, and even in neuronal secretory vesicle trafficking."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ester Fernández-Salas, Kwang S Suh, Vladislav V Speransky, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mtCLIC/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.22.11.3610-3620.2002"}], "href": "https://doi.org/10.1128/MCB.22.11.3610-3620.2002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11997498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11997498"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kwang S Suh, Michihiro Mutoh, Kunio Nagashima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The organellular chloride channel protein CLIC4/mtCLIC translocates to the nucleus in response to cellular stress and accelerates apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M311632200"}], "href": "https://doi.org/10.1074/jbc.M311632200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14610078"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14610078"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Raquel Domingo-Fernández, Rebecca C Coll, Jay Kearney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M117.797126"}], "href": "https://doi.org/10.1074/jbc.M117.797126"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28576828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28576828"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jennifer J Tung, Oliver Hobert, Mark Berryman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chloride intracellular channel 4 is involved in endothelial proliferation and morphogenesis in vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Angiogenesis (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10456-009-9139-3"}], "href": "https://doi.org/10.1007/s10456-009-9139-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19247789"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19247789"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Anjali Shukla, Mariam Malik, Christophe Cataisson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb1885"}], "href": "https://doi.org/10.1038/ncb1885"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19448624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19448624"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Qin Yao, Xun Qu, Qifeng Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CLIC4 mediates TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiation in ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or_00000469"}], "href": "https://doi.org/10.3892/or_00000469"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19639201"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19639201"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kwang S Suh, John M Crutchley, Arash Koochek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-06-1562"}], "href": "https://doi.org/10.1158/1078-0432.CCR-06-1562"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17200346"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17200346"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Marta Peretti, Marina Angelini, Nicoletta Savalli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamem.2014.12.012"}], "href": "https://doi.org/10.1016/j.bbamem.2014.12.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25546839"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25546839"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hsin-Yao Tang, Lynn A Beer, Janos L Tanyi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein isoform-specific validation defines multiple chloride intracellular channel and tropomyosin isoforms as serological biomarkers of ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteomics (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jprot.2013.06.016"}], "href": "https://doi.org/10.1016/j.jprot.2013.06.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23792823"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23792823"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mark A Berryman, James R Goldenring "}, {"type": "b", "children": [{"type": "t", "text": "CLIC4 is enriched at cell-cell junctions and colocalizes with AKAP350 at the centrosome and midbody of cultured mammalian cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Motil Cytoskeleton (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cm.10141"}], "href": "https://doi.org/10.1002/cm.10141"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14569596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14569596"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Dries Castermans, Karolien Volders, An Crepel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SCAMP5, NBEA and AMISYN: three candidate genes for autism involved in secretion of large dense-core vesicles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddq013"}], "href": "https://doi.org/10.1093/hmg/ddq013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20071347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20071347"}]}]}]}
Synonyms	HUH1, P64H1, CLIC4L, MTCLIC
Proteins	CLIC4_HUMAN
NCBI Gene ID	25932
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CLIC4 has 12,450 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 121 datasets.

Click the + buttons to view associations for CLIC4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CLIC4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CLIC4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of CLIC4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of CLIC4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CLIC4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of CLIC4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CLIC4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CLIC4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CLIC4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CLIC4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of CLIC4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CLIC4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CLIC4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with CLIC4 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CLIC4 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CLIC4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CLIC4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CLIC4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CLIC4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CLIC4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing CLIC4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing CLIC4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CLIC4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CLIC4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CLIC4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with CLIC4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with CLIC4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of CLIC4 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CLIC4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with CLIC4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CLIC4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CLIC4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CLIC4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CLIC4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CLIC4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CLIC4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CLIC4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing CLIC4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with CLIC4 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with CLIC4 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of CLIC4 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.