PXD021139

PXD021139 is an original dataset announced via ProteomeXchange.

Title	Targeting UBC9-mediated Protein Hyper-SUMOylation in Cystic Cholangiocytes Halts Polycystic Liver Disease in Experimental Models
Description	Background & Aims: polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Here, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. Methods: levels and function of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. Results: most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered the proteasome hyperactivity in cystic cholangiocytes, leading to the activation the unfolded protein response (UPR) and stress-related apoptosis.
HostingRepository	PRIDE
AnnounceDate	2020-09-29
AnnouncementXML	Submission_2020-09-29_06:26:38.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD021139
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Mikel Azkargorta
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-26 04:28:50	ID requested
⏵ 1	2020-09-29 06:26:39	announced

Lee-Law PY, Olaizola P, Caballero-Camino FJ, Izquierdo-Sanchez L, Rodrigues PM, Santos-Laso A, Azkargorta M, Elortza F, Martinez-Chantar ML, Perugorria MJ, Aspichueta P, Marzioni M, LaRusso NF, Bujanda L, Drenth JPH, Banales JM, Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models. J Hepatol, 74(2):394-406(2021) [pubmed]

submitter keyword: Hepatic cystogenesis, post-translational modifications, SUMOylation, S-adenosylmethionine (SAMe), therapy.

Felix Elortza
contact affiliation	CIC bioGUNE Proteomics Service Bizkaia Tech. Park Build. 800 48160 Derio (Spain)
contact email	felortza@cicbiogune.es
lab head
Mikel Azkargorta
contact affiliation	Proteomics Platform CIC bioGUNE
contact email	mazkargorta@cicbiogune.es
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/2020/09/PXD021139

PRIDE project URI

• PRIDE
  1. PXD021139
     1. Label: PRIDE project
     2. Name: Targeting UBC9-mediated Protein Hyper-SUMOylation in Cystic Cholangiocytes Halts Polycystic Liver Disease in Experimental Models