Critical Review Claudin Clusters as Determinants of Epithelial Barrier Function

Alexander G. Markov1 € rg R. Aschenbach2 Jo Salah Amasheh2*

1

Department of General Physiology, St. Petersburg State University, St. Petersburg, Russia 2 Institute of Veterinary Physiology, Department of Veterinary Medicine, Freie Universita€t Berlin, Berlin, Germany

Abstract Claudins are tetraspan tight junction proteins which have been attributed to primarily determine epithelial barrier function in a wide variety of different organs and tissues. Among this protein family with currently 27 members, single claudins contribute in an organ- and tissue-specific manner to defined properties such as cation-, anion- or water-selective pore functions, sealing functions or ambiguous functions. As the size of tight junction strand particles visualized by freeze-fracture electron microscopy have a diameter of approximately 10 nm, multimeric assembly of tight junction proteins appears to be a basic principle for barrier formation. Moreover, expression

patterns of different tissues showed that single claudins appear to specifically co-localize with other claudins, which indicates a cluster formation within tight junction strand particles with a fixed stoichiometry. This review provides a critical view on the current understanding of tight junction protein colocalization within strands. We analyze how tissue specific differences of claudin functions could be dependent on their specific partners for barrier formation. Furthermore, a model of claudin clusters as structural and functional units within tight C 2015 IUBMB Life, 67(1):29–35, junction strands is provided. V 2015

Keywords: membrane proteins; protein function; protein expression

Introduction Tight junctions (TJs) surround epithelial cells at the apicolateral border, and are organized in a band-like meshwork of strands. Each strand consists of two parallel rows, one in each membrane of closely spaced adhesion particles (1). Within these structures, TJ proteins have been identified including the claudin family of tetraspan TJ proteins, and members of the marvel TJ protein family, namely occludin and tricellulin. A number of studies revealed that expression of single members of the claudin family leads to formation of TJ strands connecting neighboring cells (2,3), thereby providing the main struc-

tural correlate of organ- and tissue-specific paracellular barrier and transport functions of epithelia. Overexpression studies in epithelial cell lines showed that single members of the claudin family specifically contribute to these functions; from these studies, clear evidence emerged that claudins can be functionally divided into three groups, namely claudins with sealing function (claudin-1, -3, -4, -5, -8, -11, -14 and -19), claudins providing paracellular permeability (claudin-2 and -10), and claudins with ambiguous function (claudin-7, -12, -15 and -16); the latter description derives from the observation, that both permeability-enhancing and permeability-restricting effects have been reported for these proteins in different studies (4).

C 2015 International Union of Biochemistry and Molecular Biology V

Volume 67, Number 1, January 2015, Pages 29–35 *Address correspondence to: Salah Amasheh, Institute of Veterinary Physiology, Freie Universita€t Berlin, Oertzenweg 19b, 14163 Berlin, Germany. Tel: 149-30-838-62602. Fax: 149-30-838-62610. E-mail: [email protected] Received 29 November 2014; Accepted 5 January 2015 DOI 10.1002/iub.1347 Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary.com)

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Claudins as Crucial Factors for Epithelial Barrier and Transport Evidence for the functional contribution of claudins to epithelial barrier and transport in native tissue emerged from correlation of claudin expression with functional parameters such as (1.) selective paracellular permeability in different organs, (2.) analysis of hereditary diseases, and (3.) last but not least, knockout studies (5–7).

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(7,12). Other knockout animals showed distinct dysfunctions in other organs, such as the hepatobiliary system (claudin-2 (13)), the small intestine (claudin-15 (14)), kidney (claudin-4 and claudin-16 (6,15)), and bone (claudin-18 (17)) (Table 1).

FIG 1

Results from one path impedance spectroscopy experiments providing epithelial resistance and respective predominant claudin expression in two segments of rat small intestine (*P

Claudin clusters as determinants of epithelial barrier function.

Claudins are tetraspan tight junction proteins which have been attributed to primarily determine epithelial barrier function in a wide variety of diff...
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