PXD065832

PXD065832 is an original dataset announced via ProteomeXchange.

Title	PABP1 Succinylation Alleviates Osteoarthritis by Competitively Binding IKKβ with TAK1 to Inhibit NFκB Signaling
Description	Osteoarthritis (OA) is characterized by progressive cartilage degradation and chondrocyte apoptosis, yet the regulatory mechanisms remain incompletely understood. Here, we identified lysine succinylation and its dynamic modulation by the desuccinylase sirtuin 5 (SIRT5) and the succinyltransferase carnitine palmitoyltransferase 1A (CPT1A) as critical regulators of OA progression. Inflammatory stimulation suppressed global succinylation levels in chondrocytes, accompanied by decreased CPT1A and increased SIRT5 expression. In vitro, CPT1A knockdown exacerbated extracellular matrix (ECM) degradation and apoptosis, whereas silencing SIRT5 restored succinylation and protected cartilage matrix integrity. Consistently, in vivo intra-articular knockdown of CPT1A promoted OA progression, while SIRT5 knockdown alleviated cartilage damage. Proteomic analysis identified polyadenylate-binding protein 1 (PABP1) as a key succinylated effector, with succinylation at lysine 208 essential for attenuating ECM catabolism and apoptosis. Mechanistically, succinylated PABP1 competitively bound IKKβ, displacing TGF-β activated kinase 1 (TAK1) and inhibiting NFκB signaling activation. Furthermore, we identified tiotropium via high-throughput screening as a pharmacological agent that enhances PABP1 succinylation, thereby suppressing ECM degradation and chondrocyte apoptosis both in vitro and in vivo. Population-based data from the UK Biobank indicated that tiotropium use was associated with a significantly lower risk of OA development and joint replacement. Collectively, our findings reveal a novel SIRT5/CPT1A-PABP1 succinylation axis that controls OA pathogenesis via NFκB signaling, highlighting tiotropium as a promising therapeutic candidate for OA intervention.
HostingRepository	iProX
AnnounceDate	2025-07-07
AnnouncementXML	Submission_2025-07-07_00:47:39.146.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Weiren Lan
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-07 00:47:09	ID requested
⏵ 1	2025-07-07 00:47:39	announced

Dataset with its publication pending

submitter keyword: Osteoarthritis, Succinylation, PABP1, SIRT5, CPT1A

Su'an Tang
contact affiliation	Southern Medical University
contact email	tangsan@mail2.sysu.edu.cn
lab head
Weiren Lan
contact affiliation	Southern Medical University
contact email	lanweiren26@163.com
dataset submitter

iProX dataset URI