PXD055718-1

PXD055718 is an original dataset announced via ProteomeXchange.

Title	Loss of VPS41 triggers rapid insulin degradation and dysregulated autophagy in pancreatic beta cells
Description	Vacuolar protein sorting-associated protein 41 (VPS41) has previously been established as a requirement for normal insulin secretory function in pancreatic beta-cells, with genetic deletion of VPS41 in insulinoma cells (VPS41KO) resulting in defects in insulin granule composition and secretory behaviour. In mice, VPS41 deletion in pancreatic beta-cells presented as severe hyperglycaemia due to an insulin insufficiency. Presently, we show that chronic VPS41 deletion modeled in VPS41KO insulinoma cells and aged VPS41 beta-cell knockout mice results in beta-cell dedifferentiation associated with downregulation of beta-cell identity genes and insulin granule pathway proteins. In mice, a sexually dimorphic response to beta-cell specific VPS41 deletion is observed, with young female mice exhibiting preserved insulin content, less upregulation of degradation pathway-associated proteins, and reduced ER stress, compared to young male mice. In an acute model of VPS41 depletion in vitro, VPS41-dependent loss of insulin is associated with cytosolic redistribution of mammalian target of rapamycin (mTOR), increased nuclear localisation of transcription factor E3, and impaired autophagy in VPS41KD cells. Inhibition of lysosomal degradation with chloroquine or a cysteine protease inhibitor rescues the rapidly depleted insulin content. This phenotype reflects a HOPS-dependent mechanism for insulin content regulation, with VPS41 functioning as a critical component.
HostingRepository	PRIDE
AnnounceDate	2024-12-05
AnnouncementXML	Submission_2024-12-04_18:55:50.176.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mark Larance
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-08 23:34:45	ID requested
⏵ 1	2024-12-04 18:55:50	announced

Dataset with its publication pending

submitter keyword: beta cell,Insulin, HOPS

Mark Larance
contact affiliation	Charles Perkins Centre, School of Medical Sciences, University of Sydney, Sydney, Australia.
contact email	mark.larance@sydney.edu.au
lab head
Mark Larance
contact affiliation	The University of Sydney
contact email	mark.larance@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055718
     1. Label: PRIDE project
     2. Name: Loss of VPS41 triggers rapid insulin degradation and dysregulated autophagy in pancreatic beta cells