Acetylation stimulates the epithelial sodium channel by reducing its ubiquitination and degradation. J Biol Chem 2015 May 15;290(20):12497-503
Date
03/20/2015Pubmed ID
25787079Pubmed Central ID
PMC4432271DOI
10.1074/jbc.M114.635540Scopus ID
2-s2.0-84929377394 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
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.
Author List
Butler PL, Staruschenko A, Snyder PMMESH terms used to index this publication - Major topics in bold
AcetylationAnimals
Epithelial Sodium Channels
HEK293 Cells
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Hydroxamic Acids
Ion Transport
Mice
Proteolysis
Rats
Rats, Inbred F344
Rats, Sprague-Dawley
Sodium
Ubiquitination
