PXD065838

PXD065838 is an original dataset announced via ProteomeXchange.

Title	Human Nrf1 interactome upon proteasome inhibition
Description	Nuclear factor erythroid-derived 2 related factor 1 (NFE2L1/Nrf1), an endoplasmic reticulum (ER)-associated transcription factor, is responsible for the coordinated expression of proteasome subunit genes upon proteasomal dysfunction. N-glycosylated proteins undergo protein sequence editing by peptide:N-glycanase (NGLY1)-mediated conversion of N-glycosylated asparagine residues to aspartic acid. Nrf proteins are the only transcription factors that undergo sequence editing for transcriptional activation. However, the mechanism via which sequence editing regulates the transcriptional activity of Nrf1 has remained unclear. Here, we demonstrated that sequence editing of the ninth N-glycosylation site (Asn574) in human Nrf1 is imperative for proteasome gene expression. Editing of Asn574 is essential for its interaction with host cell factor C1 (HCFC1) and O-GlcNAc transferase (OGT), which is required for sufficient proteasome expression and nuclear translocation. Furthermore, sequence editing of N-glycosylation sites other than Asn574 is required for the interaction with the co-activator CREBBP/EP300, thereby enhancing Nrf1’s transcriptional activity. Unexpectedly, the expression of Nrf1 mutants that mimic proteolytic processing by DNA-damage-inducible 1 homolog 2 and sequence editing by NGLY1 markedly diminished the growth rate, suggesting that the constitutive activation of Nrf1 exhibits cytotoxicity. Collectively, our study explains the strategy of on-demand Nrf1 activation for survival benefits. Nrf1 is synthesized as a proteasome-targeting protein and is highly glycosylated in the ER. Nrf1 is activated via sequence editing-dependent co-activator complex formation only when the proteasome needs to be compensated for.
HostingRepository	PRIDE
AnnounceDate	2025-12-14
AnnouncementXML	Submission_2025-12-13_18:05:03.481.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Akinori Endo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	N-acetylhexosaminylated residue; ubiquitination signature dipeptidyl lysine; phosphorylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-07 01:10:06	ID requested
⏵ 1	2025-12-13 18:05:04	announced

Dataset with its publication pending

submitter keyword: Nrf1, proteasome

Yukiko Yoshida
contact affiliation	Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan
contact email	yoshida-yk@igakuken.or.jp
lab head
Akinori Endo
contact affiliation	Tokyo Metropolitan Institute of Medical Science
contact email	endo-ak@igakuken.or.jp
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/12/PXD065838

PRIDE project URI

• PRIDE
  1. PXD065838
     1. Label: PRIDE project
     2. Name: Human Nrf1 interactome upon proteasome inhibition