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PXD034471-2

PXD034471 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleCoordinate control of endoplasmic reticulum chaperone biosynthesis and peptide hormone secretion revealed by a β-cell model of Prader-Willi syndrome
DescriptionPrader-Willi syndrome (PWS) is a multisystem disorder caused by loss of expression of a cluster of paternally-expressed, imprinted genes. Neonatal failure to thrive is followed by childhood-onset hyperphagia, obesity, neurobehavioral abnormalities, and hormonal deficits. Prior evidence from a mouse model with a deletion of the orthologous PWS-domain identified abnormal pancreatic islet development with deficient insulin secretion, hypoglucagonemia, and postnatal onset of progressive, lethal hypoglycemia. To investigate PWS-genes in β-cell secretory function, we used CRISPR/Cas9 genome-editing to generate isogenic, clonal INS-1 insulinoma lines with 3.16 Mb deletions of the silent, maternal (control) or active, paternal (PWS) alleles. A significant reduction in basal and glucose-stimulated insulin secretion signifies a cell autonomous insulin secretion deficit in PWS β-cells. Parallel proteome and transcriptome studies revealed reduced levels of secreted peptides and for eleven endoplasmic reticulum (ER) chaperones, including HSPA5 and HSP90B1. In contrast to dosage compensation previously seen for ER chaperones in Hspa5 or Hsp90b1 gene knockouts, compensation is precluded by the widespread deficiency of ER chaperones in PWS cells. Remarkably, but consistent with reduced ER chaperone levels, PWS β-cells are more sensitive to ER stress activation of all three regulatory pathways (XBP1, eIF2α-P, ATF6-N). Therefore, a coordinated, chronic deficit of ER chaperones in PWS β-cells is hypothesized to lead to a delay in ER transit and/or folding of insulin and other cargo along the secretory pathway. These findings provide insight into the pathophysiological basis of hormone deficits in PWS and indicate key roles for PWS-imprinted genes in β-cell secretory function.
HostingRepositoryPRIDE
AnnounceDate2023-11-14
AnnouncementXMLSubmission_2023-11-14_08:57:14.386.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterJames Moresco
SpeciesList scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationListNo PTMs are included in the dataset
InstrumentLTQ Orbitrap Elite
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-06-10 06:50:46ID requested
12023-04-11 09:09:59announced
22023-11-14 08:57:14announced2023-11-14: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: CRISPR/Cas9
genomic imprinting
hormone secretion
metabolic disease
pancreatic islet
Contact List
Robert D. Nicholls
contact affiliationDivision of Genetic and Genomic Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, USA
contact emailrobert.nicholls@chp.edu
lab head
James Moresco
contact affiliationUT Southwestern Medical Center
contact emailjames.moresco@utsouthwestern.edu
dataset submitter
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Dataset FTP location
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PRIDE project URI
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