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The Cytoplasmic Tails of Claudins Can Influence Tight Junction Barrier Properties through Effects on Protein Stability

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Abstract

The tight junction seal formed between epithelial cells varies among tissues in both tightness and ionic charge selectivity. We recently demonstrated that the extracellular domains of the claudin family of proteins are determinants of both characteristics, but in that study other unidentified domains in the claudins clearly contributed to their physiological potency. To investigate the importance of the cytoplasmic carboxyl-terminal domains in determining the degree to which a claudin can influence barrier properties, we constructed chimeras by exchanging the tails of claudin-2 and -4 and expressing them in MDCK II cells. Although swapping these domains had little effect on claudin localization, we found that the tail of claudin-2 could stabilize claudin-4, with a concomitant increase in both protein level and physiologic influence. This difference in stability was not an artifact of their chimeric structure, since metabolic radio-labeling experiments revealed that the half-life of endogenous claudin-2 is more than three times longer than claudin-4 (>12 h and ∼4 h respectively). Further, half-life was not affected by removing the carboxyl-terminal three amino acids, which form a PDZ-binding motif. The finding that cytoplasmic tails of claudins strongly influence stability reveals a potential mechanism by which cells can establish their tight junction protein composition and thus function.

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Acknowledgments

We thank the members of the Anderson laboratory for their critical insights, especially Dr. Alan S. Fanning. These studies were supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK45134 and DK55389. O.R. Colegio is a recipient of individual NRSA F31 DK61283.

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Authors and Affiliations

  1. Department of Medicine, University of North Carolina at Chapel Hill, NC, 27599, USA

    C. M. Van Itallie

  2. Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06510, USA

    O. R. Colegio

  3. Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, NC, 27599, USA

    J. M. Anderson

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  1. C. M. Van Itallie
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  2. O. R. Colegio
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  3. J. M. Anderson
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Correspondence to C. M. Van Itallie.

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Van Itallie, C.M., Colegio, O.R. & Anderson, J.M. The Cytoplasmic Tails of Claudins Can Influence Tight Junction Barrier Properties through Effects on Protein Stability. J Membrane Biol 199, 29–38 (2004). https://doi.org/10.1007/s00232-004-0673-z

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  • DOI: https://doi.org/10.1007/s00232-004-0673-z

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