CLIC5

CLIC5 exists in two alternative splice variants, a smaller CLIC5A and larger CLIC5B protein.

CLIC5A is expressed chiefly in the renal glomerulus, specifically in podocytes. Within the cell, CLIC5A is localized to the plasma membrane and the cytosol, and associates and is regulated by the actin cytoskeleton. CLIC5A can form ion channels in vitro and its channel activity is regulated by actin, though measurement of its chloride conductance in vitro suggests that CLIC5A is equally selective for cations and anions. Even so, the function of CLICs as bona fide ion channels is controversial and has been disputed.{{cite journal | vauthors = Jentsch TJ, Pusch M | title = CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease | journal = Physiological Reviews | volume = 98 | issue = 3 | pages = 1493–1590 | date = July 2018 | pmid = 29845874 | doi = 10.1152/physrev.00047.2017 | s2cid = 44165561 | doi-access = free | url = http://edoc.mdc-berlin.de/17475/1/17475oa.pdf }}{{cite journal | vauthors = Jentsch TJ | title = CLC chloride channels and transporters: from genes to protein structure, pathology and physiology | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 43 | issue = 1 | pages = 3–36 | date = January 2008 | pmid = 18307107 | doi = 10.1080/10409230701829110 | s2cid = 86536670 }}

Although chloride intracellular channel (CLIC) proteins were thought to be involved in ion transport in subcellular compartments, their actual functions suggest their role in diverse cellular and physiological functions including apoptosis and angiogenesis in CLIC1.

CLIC5A, through its interactions with the small GTPase Rac1, induces the phosphorylation of ezrin-moeisin-radixin (ERM) proteins and localized production of the phosphoinositide phosphatidylinositol-4,5-bisphosphate.{{cite journal | vauthors = Al-Momany A, Li L, Alexander RT, Ballermann BJ | title = Clustered PI(4,5)P₂ accumulation and ezrin phosphorylation in response to CLIC5A | journal = Journal of Cell Science | volume = 127 | issue = Pt 24 | pages = 5164–5178 | date = December 2014 | pmid = 25344252 | doi = 10.1242/jcs.147744 | doi-access = free }} These two events activate ezrin, enabling it to couple transmembrane proteins to the actin cytoskeleton, which could represent a mechanism by which podocyte foot processes form to enable renal filtration.{{cite journal | vauthors = Tavasoli M, Li L, Al-Momany A, Zhu LF, Adam BA, Wang Z, Ballermann BJ | title = The chloride intracellular channel 5A stimulates podocyte Rac1, protecting against hypertension-induced glomerular injury | journal = Kidney International | volume = 89 | issue = 4 | pages = 833–847 | date = April 2016 | pmid = 26924049 | doi = 10.1016/j.kint.2016.01.001 | doi-access = free }}

Two human families with loss-of-function CLIC5 mutations have been reported, with a total of 5 affected individuals. CLIC5 deficiency results in progressive hearing loss by the second decade, vestibular abnormalities, and kidney dysfunction.{{cite journal | vauthors = Wonkam-Tingang E, Schrauwen I, Esoh KK, Bharadwaj T, Nouel-Saied LM, Acharya A, Nasir A, Adadey SM, Mowla S, Leal SM, Wonkam A | display-authors = 6 | title = Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment | journal = Genes | volume = 11 | issue = 11 | pages = 1249 | date = October 2020 | pmid = 33114113 | pmc = 7690789 | doi = 10.3390/genes11111249 | doi-access = free }}{{cite journal | vauthors = Seco CZ, Oonk AM, Domínguez-Ruiz M, Draaisma JM, Gandía M, Oostrik J, Neveling K, Kunst HP, Hoefsloot LH, del Castillo I, Pennings RJ, Kremer H, Admiraal RJ, Schraders M | display-authors = 6 | title = Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5 | journal = European Journal of Human Genetics | volume = 23 | issue = 2 | pages = 189–194 | date = February 2015 | pmid = 24781754 | pmc = 4297911 | doi = 10.1038/ejhg.2014.83 }}

CLIC5A deficiency in mouse models potentiates glomerular injury in hypertension. In these mice, podocyte foot processes were also more sparse and disperse than in wild-type mice.

• Chloride channel

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• {{cite journal | vauthors = Singh H | title = Two decades with dimorphic Chloride Intracellular Channels (CLICs) | journal = FEBS Letters | volume = 584 | issue = 10 | pages = 2112–2121 | date = May 2010 | pmid = 20226783 | doi = 10.1016/j.febslet.2010.03.013 | s2cid = 21056278 | doi-access = | bibcode = 2010FEBSL.584.2112S }}
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• {{cite journal | vauthors = Shanks RA, Larocca MC, Berryman M, Edwards JC, Urushidani T, Navarre J, Goldenring JR | title = AKAP350 at the Golgi apparatus. II. Association of AKAP350 with a novel chloride intracellular channel (CLIC) family member | journal = The Journal of Biological Chemistry | volume = 277 | issue = 43 | pages = 40973–40980 | date = October 2002 | pmid = 12163479 | doi = 10.1074/jbc.M112277200 | doi-access = free }}
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• {{cite journal | vauthors = Berryman M, Bruno J, Price J, Edwards JC | title = CLIC-5A functions as a chloride channel in vitro and associates with the cortical actin cytoskeleton in vitro and in vivo | journal = The Journal of Biological Chemistry | volume = 279 | issue = 33 | pages = 34794–34801 | date = August 2004 | pmid = 15184393 | doi = 10.1074/jbc.M402835200 | doi-access = free }}
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• {{cite journal | vauthors = Singh H, Cousin MA, Ashley RH | title = Functional reconstitution of mammalian 'chloride intracellular channels' CLIC1, CLIC4 and CLIC5 reveals differential regulation by cytoskeletal actin | journal = The FEBS Journal | volume = 274 | issue = 24 | pages = 6306–6316 | date = December 2007 | pmid = 18028448 | doi = 10.1111/j.1742-4658.2007.06145.x | s2cid = 22494250 }}

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• {{MeshName|CLIC5+protein,+human}}
• {{UCSC gene info|CLIC5}}

{{NLM content}}

{{Ion channels|g4}}

Category:Ion channels

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