Acetylation Stimulates the Epithelial Sodium Channel by Reducing Its Ubiquitination and Degradation |
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Authors: | Phillip L Butler Alexander Staruschenko Peter M Snyder |
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Institution: | From the ‡Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, ;the ¶Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa 52246, and ;the §Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 |
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Abstract: | The epithelial Na+ channel (ENaC) functions as a pathway for Na+ absorption in the kidney and lung, where it is crucial for Na+ homeostasis and blood pressure regulation. ENaC is regulated in part through signaling pathways that control the ubiquitination state of ENaC lysines. A defect in ubiquitination causes Liddle syndrome, an inherited form of hypertension. Here we determined that α-, β-, and γENaC are also substrates for lysine acetylation. Trichostatin A (TSA), a histone deacetylase inhibitor, enhanced ENaC acetylation and increased ENaC abundance in the total cell lysate and at the cell surface. Moreover, TSA increased ENaC current in Fischer rat thyroid and kidney collecting duct epithelia. We found that HDAC7 is expressed in the kidney collecting duct, supporting a potential role for this histone deacetylase in ENaC regulation. HDAC7 overexpression reduced ENaC abundance and ENaC current, whereas ENaC abundance and current were increased by silencing of HDAC7. ENaC and HDAC7 form a complex, as detected by coimmunoprecipitation. We observed a reciprocal relationship between acetylation and ubiquitination; TSA reduced ENaC ubiquitination, whereas HDAC7 increased ubiquitination. By reducing ENaC ubiquitination, TSA decreased the rate of ENaC degradation. Thus, acetylation increases epithelial Na+ absorption by antagonizing ENaC ubiquitination. This stabilizes ENaC, and hence, increases its abundance at the cell surface. |
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Keywords: | Epithelial Sodium Channel (ENaC) Histone Deacetylase (HDAC) Hypertension Protein Degradation Ubiquitylation (Ubiquitination) Amiloride Lysine Acetylation Epithelia |
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