PXD017587

PXD017587 is an original dataset announced via ProteomeXchange.

Title	Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: new therapeutic targets.
Description	Polycystic liver disease (PLD) is a group of genetic disorders characterized by bile duct dilatation and/or progressive development of multiple intrahepatic fluid-filled biliary cysts (>10), which are the main cause of morbidity. Current surgical and/or pharmacological therapies exert short-term and modest benefits, and thus liver transplantation represents the only curative option. Recently, novel PLD-causative genes, encoding for endoplasmic reticulum (ER)-resident proteins involved in protein biogenesis and transport, were identified. Here, we hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. In this regard, ER stress was assessed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy; TEM) and functional (20S proteasome activity) levels in different models of PLD (i.e., human and rat). Moreover, PCK rat (animal model of PLD) was employed to determine the effects of ER stress inhibitors [4-phenylbutyric acid (4-PBA)] and/or inducers [tunicamycin (TM)] in hepatic cytogenesis and, consequently, in the progression of the disease. Likewise, the impact of the aforementioned ER stress modulators was also analyzed on the expression of unfolded protein response (UPR) factors, the 20S proteasome activity, the mechanisms involved in the maintenance of ER proteostasis and the cell fate decisions (i.e., survival/apoptosis). Interestingly, the expression levels of the UPR factors were markedly upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Additionally, cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (i.e., synthesis, folding, trafficking and degradation of nascent proteins), marked enlargement of the ER lumen (by TEM), and hyperactivation of the 20S proteasome. Notably, chronic treatment of PCK rats with 4-PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline or TM administration compared to control groups. In vitro, 4-PBA downregulated the expression (mRNA) of UPR effectors, normalized, at least in part, proteomic profiles related to protein synthesis, folding, trafficking and degradation, and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. Conclusion: Restoration of proteostasis in cystic cholangiocytes with 4-PBA halts hepatic cystogenesis, emerging as a novel and promising therapeutic strategy.
HostingRepository	PRIDE
AnnounceDate	2020-05-25
AnnouncementXML	Submission_2020-05-24_22:13:58.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Felix Elortza
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116; 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	2020-02-18 05:47:46	ID requested
⏵ 1	2020-05-24 22:13:59	announced

Santos-Laso A, Izquierdo-Sanchez L, Rodrigues PM, Huang BQ, Azkargorta M, Lapitz A, Munoz-Garrido P, Arbelaiz A, Caballero-Camino FJ, Fern, á, ndez-Barrena MG, Jimenez-Ag, ü, ero R, Argemi J, Aragon T, Elortza F, Marzioni M, Drenth JPH, LaRusso NF, Bujanda L, Perugorria MJ, Banales JM, Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: New therapeutic targets. Liver Int, 40(7):1670-1685(2020) [pubmed]

submitter keyword: Polycystic Liver Disease (PLD), Human and rat cholangiocytes, Whole cell extracts, Endoplasmic reticulum stress (ER stress), 4-phenylbutyric acid (4-PBA), proteostasis, TIMS-TOF PASEF, PEAKSQ, Perseus.

Felix Elortza
contact affiliation	CIC bioGUNE Proteomics Service Head
contact email	felortza@cicbiogune.es
lab head
Felix Elortza
contact affiliation	Proteomics Platform
contact email	felortza@cicbiogune.es
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017587
     1. Label: PRIDE project
     2. Name: Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: new therapeutic targets.