PXD032664

PXD032664 is an original dataset announced via ProteomeXchange.

Title	Proteomics of Enriched Insulin Secretory Granules Fractionated by Size Exclusion Chromotography
Description	Hybrid insulin peptides (HIPs) form in pancreatic beta-cells through the formation of peptide bonds between proinsulin fragments and other peptides. HIPs, which have been confidently identified in pancreatic islets by mass spectrometry, are targeted by CD4 T cells in subjects with Type 1 Diabetes (T1D), as well as by disease-triggering CD4 T cell clones in non-obese diabetic (NOD) mice. The mechanism(s) of HIP formation are currently poorly understood; however, it is well established that proteases can drive the formation of new peptide bonds in a side reaction during peptide bond hydrolysis. Here, we used a proteomic strategy on enriched insulin granules and identified cathepsin D (CatD) as the primary protease driving the specific formation of HIPs that are targeted by disease-relevant CD4 T cells in T1D. We also established that NOD islets deficient of cathepsin L (CatL), another protease that was implied in the formation of disease-relevant HIPs, contain elevated levels of HIPs, signifying a primary role for CatL in the proteolytic degradation of HIPs. In summary, our data suggest that CatD may be a therapeutic target in efforts to prevent or slow down the autoimmune destruction of beta-cells mediated by HIP-reactive CD4 T cells in T1D.
HostingRepository	PRIDE
AnnounceDate	2023-11-16
AnnouncementXML	Submission_2023-11-16_09:56:58.635.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Samantha Crawford
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	6550 iFunnel Q-TOF LC/MS

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-20 15:29:17	ID requested
⏵ 1	2023-11-16 09:56:59	announced

10.2337/db22-0303;

Crawford SA, Wiles TA, Wenzlau JM, Powell RL, Barbour G, Dang M, Groegler J, Barra JM, Burnette KS, Hohenstein AC, Baker RL, Tse HM, Haskins K, Delong T, Cathepsin D Drives the Formation of Hybrid Insulin Peptides Relevant to the Pathogenesis of Type 1 Diabetes. Diabetes, 71(12):2793-2803(2022) [pubmed]

submitter keyword: beta cell, proteins, insulin secretory granule, proteases

Thomas Delong
contact affiliation	University of Colorado Denver Anschutz Medical Campus, Department of Pharmaceutical Sciences, Colorado, USA
contact email	thomas.delong@cuanschutz.edu
lab head
Samantha Crawford
contact affiliation	University of Colorado Anschutz
contact email	samantha.a.crawford@cuanschutz.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/2023/11/PXD032664

PRIDE project URI

• PRIDE
  1. PXD032664
     1. Label: PRIDE project
     2. Name: Proteomics of Enriched Insulin Secretory Granules Fractionated by Size Exclusion Chromotography