First Author | Gorinski N | Year | 2020 |
Journal | J Biol Chem | Volume | 295 |
Issue | 18 | Pages | 5970-5983 |
PubMed ID | 32184353 | Mgi Jnum | J:289845 |
Mgi Id | MGI:6436454 | Doi | 10.1074/jbc.RA119.011049 |
Citation | Gorinski N, et al. (2020) DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels. J Biol Chem 295(18):5970-5983 |
abstractText | Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7 (-/-) mice. Although palmitoylation of barttin in kidneys of Zdhhc7 (-/-) animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7 (-/-) mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension. |