PXD041616

PXD041616 is an original dataset announced via ProteomeXchange.

Title	NOD Mouse Islet Peptide Content Identification
Description	Beta-cells produce hybrid insulin peptides (HIPs) by linking insulin fragments to other peptides through peptide bonds. HIPs have unique amino acid sequences and are targeted by autoreactive T cells in type 1 diabetes (T1D). Individuals with recent-onset T1D have significantly higher levels of HIP-reactive T cells in their blood compared to non-diabetic control subjects. HIP-reactive T cells have also been found in the residual pancreatic islets of deceased T1D organ donors. In non-obese diabetic (NOD) mice, a major T1D animal model, several CD4 T cell clones that trigger diabetes have been shown to target HIPs. Through mass spectrometry, a subgroup of HIPs containing N-terminal amine groups of various peptides linked to aspartic acid residues of insulin C-peptide has been detected in NOD islets. Our research reveals that these HIPs form spontaneously in beta-cells via an aspartic anhydride intermediate mechanism. This process leads to the creation of a regular HIP with a standard peptide bond and a HIP-isomer (isoHIP) with an isopeptide bond linked to the carboxylic acid side-chain of the aspartic acid residue. Our mass spectrometric analyses confirmed the presence of both HIP isomers in murine islets, thereby validating the occurrence of this new reaction mechanism in beta-cells. The spontaneous formation of neoepitopes through the development of new peptide bonds within cells may contribute to the pathogenesis of T1D and other autoimmune diseases.
HostingRepository	PRIDE
AnnounceDate	2024-10-08
AnnouncementXML	Submission_2024-10-08_11:13:55.306.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	6520A Quadrupole Time-of-Flight LC/MS

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-18 01:16:33	ID requested
⏵ 1	2024-10-08 11:13:56	announced

Crawford SA, Groegler J, Dang M, Michel C, Powell RL, Hohenstein AC, Reyes K, Haskins K, Wiles TA, Delong T, Hybrid insulin peptide isomers spontaneously form in pancreatic beta-cells from an aspartic anhydride intermediate. J Biol Chem, 299(11):105264(2023) [pubmed]

10.1016/j.jbc.2023.105264;

submitter keyword: HIPs, NOD mouse, islet cells, peptides,LC-MSMS

Thomas Delong
contact affiliation	Department of Pharmaceutical Sciences, University of Colorado - Anschutz Medical Campus, Aurora, CO, 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

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PRIDE project URI

• PRIDE
  1. PXD041616
     1. Label: PRIDE project
     2. Name: NOD Mouse Islet Peptide Content Identification