PXD026301-1

PXD026301 is an original dataset announced via ProteomeXchange.

Title	Comparative proteomics reveal elevated CCN2 in NGLY1 deficient cells
Description	N-glycanase 1(NGLY1) catalyzes the removal of N-linked glycans from newly synthesized or misfolded protein to exert protein quality control function via the process of endoplasmic reticulum-associated degradation (ERAD). NGLY1 deficiency (OMIM 615273) is a newly diagnosed rare genetic disorder with ~60 patients worldwide to date. The affected individuals present a broad spectrum of clinical features, including developmental delay, seizures, muscle weakness, liver failure, and the reduced secretion of sweats and tears. Recent studies explored several possible molecular mechanisms of NGLY1 deficiency including in vivo proteostasis, mitochondrial homeostasis, innate immunity, water and ion transport, with the goal of linking these findings to the pathophysiology of the disease. This study focuses on the dysregulation of ERAD in NGLY1 deficiency. We demonstrate the abnormal accumulation of ERAD substrates in NGLY1 deficient cells. Comprehensive global quantitative proteomics discovered elevated levels of novel endogenous proteins in NGLY1 defective human and mouse cells. Further biological validation assays confirmed the altered abundance of several key candidates’ that were observed in the isobarically labeled proteomic experiments. CCN2 was selected for further analysis due to its high fold change in different cell models of NGLY1 deficiency. Functional assays show elevated CCN2 and over-stimulated TGF-β signaling in NGLY1 deficient cells. Given the important role of CCN2 and TGF-β pathway in mediating systemic fibrosis, we propose a potential link of increased CCN2 and TGF-β signaling to microscopic liver fibrosis in NGLY1 patients.
HostingRepository	PRIDE
AnnounceDate	2021-12-21
AnnouncementXML	Submission_2021-12-21_07:31:02.761.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD026301
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Ling Li
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-05-26 23:51:36	ID requested
⏵ 1	2021-12-21 07:31:03	announced

Dataset with its publication pending

submitter keyword: NGLY1, proteomics, CCN2, TGF-β signaling, fibrosis

Ping He
contact affiliation	Department of Pre-Clinical Medicine, Lake Erie College of Osteopathic Medicine
contact email	phe@lecom.edu
lab head
Ling Li
contact affiliation	Cleveland Clinic
contact email	lil5@ccf.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026301
     1. Label: PRIDE project
     2. Name: Comparative proteomics reveal elevated CCN2 in NGLY1 deficient cells