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Merck

DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels.

The Journal of biological chemistry (2020-03-19)
Nataliya Gorinski, Daniel Wojciechowski, Daria Guseva, Dalia Abdel Galil, Franziska E Mueller, Alexander Wirth, Stefan Thiemann, Andre Zeug, Silke Schmidt, Monika Zareba-Kozioł, Jakub Wlodarczyk, Boris V Skryabin, Silke Glage, Martin Fischer, Samer Al-Samir, Nicole Kerkenberg, Christa Hohoff, Weiqi Zhang, Volker Endeward, Evgeni Ponimaskin
RESUMEN

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.