PXD041504

PXD041504 is an original dataset announced via ProteomeXchange.

Title	Neutrophil-derived PAD4 induces citrullination of CKMT1 in epithelial cells to exacerbate mucosal inflammation
Description	Objective Increased neutrophil extracellular trap-osis (NETosis) is a hallmark of inflammatory bowel disease (IBD). However, the mechanisms of NETosis formation and its detrimental effect on the intestinal epithelium remain poorly understood. Design Dextran sulfate sodium (DSS) induce colitis in peptidyl-arginine deiminase-4 deficient (PAD4-/-) and wild-type (WT) mice. PAD4, NETosis and citrullination levels were detected in mice and human volunteers. Citrullination analysis and single-cell RNA-sequencing (scRNA-seq) were performed to explore the target of PAD4 during NETosis formation. The effect of this citrullinated target in the intestinal epithelium during the pathogenesis of IBD was validated both in vivo and in vitro. Results The levels of NETosis and citrullination were improved in IBD patients, which was positively associated with endoscopic inflammation scores. Deleting PAD4 alleviated colonic inflammation and intestinal barrier dysfunctions. In citrullination analysis, R243 of mitochondrial creatine kinase 1 (CKMT1) was identified as the potential target of PAD4 during NETosis. The scRNA-seq data further indicated that PAD4 in neutrophils contributed to the increase of epithelia (Nos2+ Clca3b+) and the decrease of distal immature epithelia. PAD4-mediated NETosis contributed to the destruction of intestinal barriers and increase of apoptosis as well as lower level of CKMT1 protein in vitro. Finally, mice with intestinal epithelial-specific ablation of CKMT1 were used to verify its detrimental role in the development of IBD, which was also validated by the moderate correlation between CKMT1 and endoscopic scores in IBD patients.
HostingRepository	PRIDE
AnnounceDate	2025-06-09
AnnouncementXML	Submission_2025-06-08_16:11:24.720.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shuling Wang
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	L-citrulline
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-13 01:25:11	ID requested
⏵ 1	2025-06-08 16:11:25	announced

10.1038/s41423-024-01158-6;

Wang S, Song Y, Wang Z, Chang X, Wu H, Yan Z, Wu J, He Z, Kang L, Hu W, Xia T, Li Z, Ren X, Bai Y, Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease. Cell Mol Immunol, 21(6):620-633(2024) [pubmed]

submitter keyword: peptidyl-arginine deiminase-4

citrullination

mitochondrial creatine kinase 1

neutrophil extracellular traps

intestinal epithelial cells

inflammatory bowel disease

Shuling Wang
contact affiliation	Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
contact email	wangshuling0000@126.com
lab head
Shuling Wang
contact affiliation	The First Affiliated Hospital of Naval Medical University
contact email	wangshuling0000@126.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041504
     1. Label: PRIDE project
     2. Name: Neutrophil-derived PAD4 induces citrullination of CKMT1 in epithelial cells to exacerbate mucosal inflammation