PXD040179-1

PXD040179 is an original dataset announced via ProteomeXchange.

Title	Peptidylarginine deiminase 2 (PADI2) is a key regulator for osteoblast differentiation and bone formation through the maintenance of citrullination-mediated RUNX2 stability
Description	Peptidylarginine deiminase (PADI) 2 catalyzes the posttranslational conversion of peptidyl-arginine to peptidyl-citrulline, a process called citrullination. However, the exact function of PADI2 in bone development and bone homeostasis remains unknown. In this study, we found that Padi2 deficiency lead to loss of bone mass and cleidocranial dysplasia (CCD)-like phenotype with delayed calvarial ossification and clavicular hypoplasia due to impaired osteoblast differentiation. Mechanistically, Padi2 depletion drastically reduced RUNX2 protein level and PADI2 stabilized RUNX2 from ubiquitin-proteasomal degradation. Furthermore, we identified a new modification at RUNX2, citrullination of arginine and its conversion to citrulline by PADI2. PADI2 citrullinates RUNX2 via a direct physical interaction and the citrullination sites at RUNX2 by PADI2 were identified by high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Interestingly, in mouse RUNX2 isoform 1 (528 a.a), loss of R381, a citrullination site by PADI2, drastically reduced RUNX2 protein levels, indicating that the citrullination of RUNX2 by PADI2 is required for the maintenance of RUNX2 protein stability. Collectively, our study demonstrates that PADI2-mediated citrullination play key roles in bone formation and bone homeostasis. Also, CCD may result from functional defects of RUNX2 by Padi2 deficiency. These insights into the role of PADI2 in postnatal bone formation and homeostasis and CCD pathogenesis may assist in the development of new therapies for bone diseases including CCD.
HostingRepository	PRIDE
AnnounceDate	2023-10-24
AnnouncementXML	Submission_2023-10-24_11:56:48.260.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD040179
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Byung-gyukim
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	deamidated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-16 10:11:28	ID requested
⏵ 1	2023-10-24 11:56:49	announced
2	2023-11-14 09:08:48	announced	2023-11-14: Updated project metadata.

10.6019/PXD040179;

Kim HJ, Shin HR, Yoon H, Park MS, Kim BG, Moon JI, Kim WJ, Park SG, Kim KT, Kim HN, Choi JY, Ryoo HM, Peptidylarginine deiminase 2 plays a key role in osteogenesis by enhancing RUNX2 stability through citrullination. Cell Death Dis, 14(8):576(2023) [pubmed]

submitter keyword: Citrullination, PTM,PADI2,LC-MSMS,Runx2

Hyun-MoRyoo
contact affiliation	Basic Research Lab for “Epigenetic Regeneration of Aged Skeleto-Muscular System (ERASMUS)”, Department of Molecular Genetics and Dental Pharmacology, School of Dentistry, Dental Research Institute, Seoul National University, Seoul, South Korea
contact email	hmryoo@snu.ac.kr
lab head
Byung-gyukim
contact affiliation	Center for genomic integrity (CGI), Institute of basic science (IBS), UNIST, Ulsan, 44919, Republic of Korea
contact email	goldenlion@ibs.re.kr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040179
     1. Label: PRIDE project
     2. Name: Peptidylarginine deiminase 2 (PADI2) is a key regulator for osteoblast differentiation and bone formation through the maintenance of citrullination-mediated RUNX2 stability