PXD040450

PXD040450 is an original dataset announced via ProteomeXchange.

Title	Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization, proteomics-based profiling of Ctns KO mouse proximal tubule cells (mPTCs)
Description	Differentiation is critical for epithelial cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, lysosomal cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of Rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in a zebrafish model of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 signaling and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.
HostingRepository	PRIDE
AnnounceDate	2025-05-13
AnnouncementXML	Submission_2025-05-13_06:06:38.519.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Oksana Glushchenko
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-27 06:09:16	ID requested
⏵ 1	2025-05-13 06:06:39	announced

10.1038/s41467-023-39261-3;

Berquez M, Chen Z, Festa BP, Krohn P, Keller SA, Parolo S, Korzinkin M, Gaponova A, Laczko E, Domenici E, Devuyst O, Luciani A, Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization. Nat Commun, 14(1):3994(2023) [pubmed]

submitter keyword: Cystinosis, Fanconi syndrome, CTNS, mTORC1, kidney failure

Alessandro Luciani
contact affiliation	Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland
contact email	alessandro.luciani@physiol.uzh.ch
lab head
Oksana Glushchenko
contact affiliation	Insilico Medicine
contact email	glushchenko.oksana.it@gmail.com
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/2025/05/PXD040450

PRIDE project URI

• PRIDE
  1. PXD040450
     1. Label: PRIDE project
     2. Name: Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization, proteomics-based profiling of Ctns KO mouse proximal tubule cells (mPTCs)