PXD034471-2

PXD034471 is an original dataset announced via ProteomeXchange.

Title	Coordinate control of endoplasmic reticulum chaperone biosynthesis and peptide hormone secretion revealed by a β-cell model of Prader-Willi syndrome
Description	Prader-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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:57:14.386.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	James Moresco
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-10 06:50:46	ID requested
1	2023-04-11 09:09:59	announced
⏵ 2	2023-11-14 08:57:14	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: CRISPR/Cas9

genomic imprinting

hormone secretion

metabolic disease

pancreatic islet

Robert D. Nicholls
contact affiliation	Division of Genetic and Genomic Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, USA
contact email	robert.nicholls@chp.edu
lab head
James Moresco
contact affiliation	UT Southwestern Medical Center
contact email	james.moresco@utsouthwestern.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/2023/04/PXD034471

PRIDE project URI

• PRIDE
  1. PXD034471
     1. Label: PRIDE project
     2. Name: Coordinate control of endoplasmic reticulum chaperone biosynthesis and peptide hormone secretion revealed by a β-cell model of Prader-Willi syndrome