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J. Biol. Chem., Vol. 282, Issue 38, 28149-28156, September 21, 2007

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Small Heat Shock Protein A-crystallin Regulates Epithelial Sodium Channel Expression^*

Ossama B. Kashlan¹², Gunhild M. Mueller², Mohammad Z. Qamar, Paul A. Poland, Annette Ahner, Ronald C. Rubenstein^¶, Rebecca P. Hughey^||3, Jeffrey L. Brodsky, and Thomas R. Kleyman^||

From the Renal-Electrolyte Division, Department of Medicine and the Departments of Biological Sciences and ^||Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and the ^¶Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Integral membrane proteins are synthesized on the cytoplasmic face of the endoplasmic reticulum (ER). After being translocated or inserted into the ER, they fold and undergo post-translational modifications. Within the ER, proteins are also subjected to quality control checkpoints, during which misfolded proteins may be degraded by proteasomes via a process known as ER-associated degradation. Molecular chaperones, including the small heat shock protein A-crystallin, have recently been shown to play a role in this process. We have now found that A-crystallin is expressed in cultured mouse collecting duct cells, where apical Na⁺ transport is mediated by epithelial Na⁺ channels (ENaC). ENaC-mediated Na⁺ currents in Xenopus oocytes were reduced by co-expression of A-crystallin. This reduction in ENaC activity reflected a decrease in the number of channels expressed at the cell surface. Furthermore, we observed that the rate of ENaC delivery to the cell surface of Xenopus oocytes was significantly reduced by co-expression of A-crystallin, whereas the rate of channel retrieval remained unchanged. We also observed that A-crystallin and ENaC co-immunoprecipitate. These data are consistent with the hypothesis that small heat shock proteins recognize ENaC subunits at ER quality control checkpoints and can target ENaC subunits for ER-associated degradation.

Received for publication, April 24, 2007 , and in revised form, July 19, 2007.

^* This work was supported in part by Grants GM75061 (to J. L. B.), DK065161 (to T. R. K. and R. P. H.), and DK58046 (to R. C. R.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Grants DK061296 and DK066883 and a Scientist Development grant from the American Heart Association.

² These authors contributed equally to this work.

³ To whom correspondence should be addressed: 933 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-383-8949; Fax: 412-383-8956; E-mail: hughey{at}dom.pitt.edu.

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