期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 18, 页码 5970-5983出版社
ELSEVIER
DOI: 10.1074/jbc.RA119.011049
关键词
post-translational modification (PTM); ion channel; enzyme; kidney metabolism; mouse genetics; Bartter syndrome type IV; barttin; chloride channel ClC-K; palmitoylation; palmitoyltransferase DHHC7; hypertension; renal dysfunction; nephropathy
资金
- Deutsche Forschungsgemeinschaft (DFG) [Po732, ZH 34/3-1]
- Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience of the University of Munster
- Interdisciplinary Centre for Clinical Research (IZKF) of the University of Munster Medical School [Zha3-005-14]
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.
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