PXD041331

PXD041331 is an original dataset announced via ProteomeXchange.

Title	ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation
Description	The endoplasmic reticulum (ER) is a multifaceted organelle that plays an essential role in cellular processes such as protein folding, modification, and trafficking. It also acts as a proteostasis sensor and contributes to adaptation responses to maintain cellular homeostasis. The transcription factor NRF1 resides in the ER and is constantly transported from the ER to the cytosol for proteasomal degradation. However, when the proteasome function is defective, NRF1 escapes degradation and undergoes proteolytic cleavage by the protease DDI2, generating a transcriptionally active form that restores proteostasis, including proteasome function. Despite the importance of NRF1 in these processes, the mechanisms that regulate its proteolytic activation and transcriptional potential remain poorly understood. In this study, we utilized a functional molecular approach to elucidate the critical steps involved in NRF1 cleavage. Our results demonstrate that the ER is a crucial regulator of NRF1 function, orchestrating its ubiquitination by the ER-localized E3 ubiquitin ligase HRD1, a component of the ER-associated degradation (ERAD) pathway. Furthermore, we show that HRD1-mediated NRF1 ubiquitination is necessary for DDI2-mediated processing in cells. Notably, we found that the fusion of a ubiquitin moiety to NRF1 was sufficient to promote its proteolytic maturation by DDI2, thus bypassing the requirement for its trafficking to the ER. Our findings highlight the intricate mechanism by which NRF1 is activated by DDI2 and coordinates the transcriptional activity of an adaptation response in cells and suggest potential avenues for therapeutic interventions in conditions associated with proteasome impairment.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:14:29.268.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD041331
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Manfredo Quadroni
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	N-acetylaminoglucosylated residue; ubiquitinylated lysine; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion; Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-04 09:10:15	ID requested
1	2023-09-05 06:56:04	announced
⏵ 2	2023-11-14 07:14:29	announced	2023-11-14: Updated project metadata.

10.6019/PXD041331;

submitter keyword: ERAD, ubiquitination,NRF1, DDI2, proteostasis

Fabio Martinon
contact affiliation	University of Lausanne, Department of Immunobiology, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland
contact email	fabio.martinon@unil.ch
lab head
Manfredo Quadroni
contact affiliation	University of Lausanne
contact email	manfredo.quadroni@unil.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041331
     1. Label: PRIDE project
     2. Name: ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation