PXD017231

PXD017231 is an original dataset announced via ProteomeXchange.

Title	DHHC7-mediated palmitoylation of barttin is a risk factor for Bartter syndrome
Description	Chloride permeability in the thin and thick ascending limbs of the loop of Henle is a crucial component for urine concentration, with ClC-K/barttin chloride channels as a central component in establishing the cortico-medullary osmotic gradient. Barttin is an accessory subunit of human ClC-K channels, promoting trafficking of the ClC-K/barttin complex to the plasma membrane, increasing channel stability, and switching ClC-K/barttin channels into an active state. Barttin undergoes post-translational palmitoylation, which is essential for channel activation. Here, we identified DHHC7 as a major barttin palmitoyl-acyltransferase, the depletion of which reduced barttin palmitoylation and the macroscopic current amplitudes in cells expressing ClC-K/barttin channels. To investigate a functional role of barttin palmitoylation in vivo, we established Zdhhc7-/- mice. Although barttin palmitoylation was significantly decreased in the kidneys of Zdhhc7-/- animals, it did not result in any pathological consequences for kidney structure or function under physiological conditions. However, when Zdhhc7-/- animals were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) Type IV with mild progression. Notably, decreased barttin palmitoylation was also found for the R8L barttin mutant identified in human BS Type IV. These data suggest that barttin palmitoylation plays an important role in chloride channel dysfunction in certain variants of BS. Thus, our study provides evidence of the downregulation of barttin palmitoylation as a possible mechanism in the etiology of BS, making the restoration of barttin palmitoylation a promising clinical strategy for the treatment of Type IV BS.
HostingRepository	PRIDE
AnnounceDate	2020-03-31
AnnouncementXML	Submission_2020-03-30_23:41:45.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Monika Zareba-Koziol
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	N-ethylmaleimide derivatized cysteine; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-21 03:59:21	ID requested
⏵ 1	2020-03-30 23:41:46	announced

Gorinski N, Wojciechowski D, Guseva D, Abdel Galil D, Mueller FE, Wirth A, Thiemann S, Zeug A, Schmidt S, Zareba-Kozio, ł M, Wlodarczyk J, Skryabin BV, Glage S, Fischer M, Al-Samir S, Kerkenberg N, Hohoff C, Zhang W, Endeward V, Ponimaskin E, DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels. J Biol Chem, 295(18):5970-5983(2020) [pubmed]

submitter keyword: DHHC7, palmitoylation, barttin, Bartter syndrome, mass spectrometry,PANIMoni

Jakub Włodarczyk
contact affiliation	Nencki Institute of Experimental Biology, PAS
contact email	j.wlodarczyk@nencki.edu.pl
lab head
Monika Zareba-Koziol
contact affiliation	Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, PAS
contact email	m.zareba-koziol@nencki.gov.pl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017231
     1. Label: PRIDE project
     2. Name: DHHC7-mediated palmitoylation of barttin is a risk factor for Bartter syndrome