PXD038554

PXD038554 is an original dataset announced via ProteomeXchange.

Title	Palmitoylation couples insulin hypersecretion with β-cell failure in diabetes
Description	Hyperinsulinemia often precedes type 2 diabetes but its role in disease progression is unknown. Palmitoylation, a protein modification implicated in regulated exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). We found altered APT1 biology in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic human islets caused insulin hypersecretion. Chow fed global and islet specific APT1 knockout mice had enhanced glucose tolerance due to islet autonomous increased glucose-stimulated insulin secretion. APT1 deficiency did not affect islet calcium dynamics but prolonged insulin granule fusion. Using palmitoylation proteomics, we identified Scamp1 as an APT1 substrate that localized to insulin secretory granules. Knockdown of Scamp1 caused insulin hypersecretion. APT1 deficient insulinoma cells subjected to nutrient excess had increased apoptosis, and expression of a mutated Scamp1 incapable of being palmitoylated in APT1 deficient cells rescued insulin hypersecretion and nutrient induced apoptosis. Compared to APT1 sufficient controls, high fat fed islet specific APT1 knockout mice and global APT1 deficient db/db mice showed increased -cell failure. These findings suggest that the depalmitoylation enzyme APT1 is regulated in human islets, and that APT1 deficiency causes insulin hypersecretion leading to -cell failure, modeling the evolution of some forms of human type 2 diabetes.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:13:42.370.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD038554
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Qiang Zhang
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-05 06:25:08	ID requested
1	2023-11-05 05:24:31	announced
⏵ 2	2023-11-14 09:13:51	announced	2023-11-14: Updated project metadata.

10.6019/PXD038554;

Dong G, Adak S, Spyropoulos G, Zhang Q, Feng C, Yin L, Speck SL, Shyr Z, Morikawa S, Kitamura RA, Kathayat RS, Dickinson BC, Ng XW, Piston DW, Urano F, Remedi MS, Wei X, Semenkovich CF, cell failure in diabetes. Cell Metab, 35(2):332-344.e7(2023) [pubmed]

submitter keyword: proteomics,Palmitoylation, pancreatic islet, insulin, diabetes

Clay Semenkovich
contact affiliation	Division of Endocrinology, Metabolism & Lipid Research, Washington University, St. Louis Department of Cell Biology & Physiology, Washington University, St. Louis
contact email	csemenko@wustl.edu
lab head
Qiang Zhang
contact affiliation	Washington University in St. Louis
contact email	zhang.qiang@wustl.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038554
     1. Label: PRIDE project
     2. Name: Palmitoylation couples insulin hypersecretion with β-cell failure in diabetes