title: Acetylation stimulates the epithelial sodium channel by reducing its ubiquitination and degradation.
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.
authors: From the Departments of Internal Medicine and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
authors: Phillip L
authors: PL
authors: Butler
authors: the Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors: Alexander
authors: A
authors: Staruschenko
authors: 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 peter-snyder@uiowa.edu.
authors: Peter M
authors: PM
authors: Snyder
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D051379:Mice; D059748:Proteolysis; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*
chemical_list: D053503:Epithelial Sodium Channels; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D012964:Sodium; C543273:HDAC7 protein, human; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases
keywords: Amiloride; Epithelia; Epithelial Sodium Channel (ENaC); Histone Deacetylase (HDAC); Hypertension; Lysine Acetylation; Protein Degradation; Ubiquitylation (Ubiquitination)