PXD069246

PXD069246 is an original dataset announced via ProteomeXchange.

Title	TIGAR Regulates Intestinal Mucus Barrier Integrity by Inhibiting Lactylation of G6PD/6PGD in Ulcerative Colitis
Description	Oxidative stress and metabolic dysregulation in goblet cells represent significant contributors to the pathogenesis of ulcerative colitis (UC). TIGAR (TP53-induced glycolysis and apoptosis regulator) plays a critical role as a metabolic regulatory enzyme by promoting NADPH synthesis, thereby counteracting oxidative stress. However, the precise mechanisms through which TIGAR regulates NADPH synthesis and its impact on UC remain incompletely understood. Here, we demonstrate that TIGAR inhibits the lactylation of glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD), both pivotal enzymes in the NADPH biosynthesis pathway, hence preserving their enzymatic activities. We further identify specific lactylation sites at lysine 453 (K453) in G6PD and lysine 38 (K38) in 6PGD. Lactylation modifications impact the formation of G6PD homodimers and the binding of 6PGD with NADP+. In UC mice, persistently low TIGAR expression results in elevated lactic acid levels, which enhance the lactylation of G6PD and 6PGD, inhibit NADPH synthesis, and exacerbate oxidative stress in goblet cells. Consequently, these alterations lead to a reduction in thioredoxin 1 (Trx1) reductase activity, inducing S-nitrosylation of anterior gradient homolog 2 (AGR2), a key enzyme involved in MUC2 modification, thus impeding mature MUC2 production and compromising the integrity of the intestinal mucus barrier. Overall, our study elucidates the critical mechanisms by which TIGAR regulates NADPH synthesis, provides novel insights into how TIGAR maintains cellular redox homeostasis, and offers experimental evidence for considering TIGAR as a potential target for UC therapy.
HostingRepository	iProX
AnnounceDate	2025-10-09
AnnouncementXML	Submission_2025-10-09_02:19:15.771.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sen Su
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	S-nitrosyl-L-cysteine
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-09 02:19:01	ID requested
⏵ 1	2025-10-09 02:19:16	announced

Dataset with its publication pending

submitter keyword: TIGAR, lactylation, 6PGD, G6PD, Ulcerative Colitis

Xi Peng
contact affiliation	Clinical Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University)
contact email	pxlrmm@tmmu.edu.cn
lab head
Sen Su
contact affiliation	Southwest Hospital, Third Military Medical University (Army Medical University)
contact email	1441suse@163.com
dataset submitter

iProX dataset URI