The reference OMIM entry for this protein is 606536

Chloride intracellular channel 4; clic4
Chloride intracellular channel, mitochondrial; mtclic

DESCRIPTION

Chloride intracellular channels (CLICs), such as CLIC4, have actions distinct from traditional cell membrane chloride channels. These include formation of ion channels in intracellular organelles and roles in membrane trafficking, apoptosis, and cell differentiation (summary by Chalothorn et al., 2009).

CLONING

Intracellular chloride channels, such as bovine p64 and human CLIC1 (602872), are found in several types of vacuolar organelles, where they contribute to electrolyte composition and acidification of intravesicular spaces. By screening a pancreatic carcinoma cDNA library with bovine p64, Edwards (1999) isolated a cDNA encoding human CLIC4, which he referred to as PH3 and H1. The 253-amino acid CLIC4 protein is 97%, 67%, and 66% identical to rat H1 and human CLIC1 and CLIC2 (300138), respectively. CLIC4 has 5 potential phosphorylation sites. Northern blot analysis revealed ubiquitous expression of a 4.5-kb CLIC4 transcript, with prominent expression in heart, placenta, and skeletal muscle as well as pancreatic carcinoma cells. SDS-PAGE and Western blot analysis showed expression of a 31-kD protein. Confocal microscopy demonstrated colocalization with CAV1 (601047) in caveolae of pancreatic cancer cells; however, unlike rat H1, CLIC4 was not localized in the endoplasmic reticulum. Immunofluorescence microscopy of kidney sections indicated diffuse expression of CLIC4 in the apical domain of proximal tubule cells, with lower vesicular expression in glomeruli and distal nephron. Chuang et al. (1999) also cloned CLIC4, which they termed p64H1, using a yeast 2-hybrid screen of a bovine retinal cDNA library with the C terminus of rhodopsin (RHO; 180380) as bait, followed by probing a human retina cDNA library. Northern blot analysis indicated high expression in bovine brain and retina. Immunohistochemical analysis demonstrated high expression in the limbic system of rat brain. Fernandez-Salas et al. (1999) cloned mouse Clic4, which they called mtClic or mc3s5. The deduced 253-amino acid protein has 2 transmembrane domains, the second of which contains hydrophilic amino acids thought to constitute the pore of the chloride channel. Northern blot analysis showed variable mtClic expression, with highest levels in heart, lung, liver, kidney, and skin. Fluorescence-labeled mtClic and endogenous mtClic localized to the cytoplasm and mitochondria of mouse keratinocytes. MtClic localized to the mitochondrial and cytoplasmic fractions of rat liver homogenates. Immunofluorescence revealed colocalization of mouse mtClic with cytochrome oxidase (see MTCO1; 516030) in keratinocyte mitochondria, and this finding was confirmed in purified mitochondria from rat liver. Using immunoelectron microscopy, Fernandez-Salas et al. (2002) localized CLIC4 in human keratinocytes to mitochondrial cristae and the peripheral inner mitochondrial membrane. There was no significant labeling of the outer mitochondrial membrane.

GENE FUNCTION

Using differential display, Fernandez-Salas et al. (1999) found that mtClic was upregulated in differentiating wildtype mouse keratinocytes, but not in p53 (TP53; 191170)-null mouse keratinocytes. Overexpression of p53 in keratinocytes induced mtClic mRNA and protein. Exogenous human recombinant TNF-alpha (TNF; 191160) also upregulated mtClic mRNA and protein in mouse keratinocytes. Fernandez-Salas et al. (2002) found that mtCLIC expression in mouse keratinocytes and in a human osteosarcoma ... More on the omim web site

Subscribe to this protein entry history

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 606536 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).