PXD048013

PXD048013 is an original dataset announced via ProteomeXchange.

Title	Disruption of the human Cystin-1 myristoyl-electrostatic switch causes autosomal recessive polycystic kidney disease (ARPKD)
Description	Autosomal recessive polycystic kidney disease (ARPKD; MIM#263200) is primarily caused by pathogenic variants in PKHD1, which encodes fibrocystin/polyductin (FPC). The Cys1cpk/cpk (cpk) mouse expresses a renal lesion that closely phenocopies ARPKD. Cys1-encoded cystin is a myristoylated protein that traffics to the primary cilium and the nucleus, where it regulates gene expression. We recently described the first human patient with ARPKD due to a homozygous CYS1 splicing variant. Here we present two siblings with ARPKD and homozygosity for a CYS1 c.4G>A (p.G2S) variant, which disrupts the G2 myristoylation site within the predicted N-terminal myristylation motif, MGxxxSx. Alignment of 97 vertebrate cystin protein sequences showed high conservation of a putative myristoyl-electrostatic switch that can regulate reversible protein binding to membranes. The conserved region includes the N-myristylation site and an adjacent arginine-rich stretch flanked by serine-8 (S8) and -17 (S17) residues. Using immunofluorescence and site-directed mutagenesis, we confirmed that S17 phosphorylation modulates cystin membrane association and intracellular trafficking. In turn, optogenetic activation of ciliary cAMP signaling reduced the cystin ciliary localization in a PKA-dependent manner. Tandem affinity purification (TAP) and mass spectroscopy identified the protein phosphatase PPM1A as a cystin-interacting partner. Inhibition of PPM1A with sanguinarine impeded cystin S17 de-phosphorylation confirming functional interaction. Our study demonstrates that cystin intracellular trafficking and nuclear function are regulated by a myristoyl-electrostatic switch mechanism, and further supports CYS1 as a disease-causing gene for human ARPKD, providing the first mechanistic insight for disease pathogenesis.
HostingRepository	PRIDE
AnnounceDate	2026-04-13
AnnouncementXML	Submission_2026-04-12_18:12:41.508.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Landon Wilson
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-20 12:45:02	ID requested
⏵ 1	2026-04-12 18:12:42	announced

Yang C, Harafuji N, Watts JA, Tao B, Moran C, Clements J, Price K, Laucevicius A, Burrill N, Gebb J, Soni S, Oliver E, Savla JJ, Christ L, Moldenhauer J, Hartung EA, Didier R, Santani A, Sandford RN, Selkirk L, Radley JA, Mann K, Simonicova I, Karl R, Kariat Ashraf AP, Wachten D, Wilson L, Bebok Z, Caldovic L, Guay-Woodford LM, Disruption of the human cystin-1 myristoyl-electrostatic switch causes polycystic kidney disease that phenocopies autosomal recessive polycystic kidney disease. Kidney Int, 109(5):939-956(2026) [pubmed]

10.1016/j.kint.2026.01.023;

submitter keyword: ARPKD, myristoyl-electrostatic switch, PKA-phosphorylation, PPM1A-dephosphorylation, cystin, Cystin-1

Lisa Guay-Woodford
contact affiliation	Center for Translational Research, Children’s National Research Institute, Children’s National Hospital, Washington,DC, United States & Children’s Hospital of Philadelphia, Philadelphia, PA, United States
contact email	guaywoodfl@chop.edu
lab head
Landon Wilson
contact affiliation	University of Alabama at Birmingham
contact email	empy1977@uab.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/04/PXD048013

PRIDE project URI

• PRIDE
  1. PXD048013
     1. Label: PRIDE project
     2. Name: Disruption of the human Cystin-1 myristoyl-electrostatic switch causes autosomal recessive polycystic kidney disease (ARPKD)