PXD051146

PXD051146 is an original dataset announced via ProteomeXchange.

Title	Pathogenic Proteotoxicity of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy
Description	RNA splicing and protein degradation systems allow functional adaptation of the proteome in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here, we show that impaired spliceosome assembly caused by USP39 deficiency leads to a pathogenic splicing profile characterized by the use of cryptic 5′ splice sites. Importantly, disruptive cryptic variants evade mRNA surveillance pathways and are translated into misfolded proteins. These spurious isoforms disrupt proteostasis causing proteotoxic aggregates, ER stress and CHOP-mediated cell death. In response to impaired splicing, eukaryotic cells enhance ubiquitination and ER-phagy to alleviate the pathogenic translation of proteotoxic exons. Our findings show how cryptic splicing-inducedproteotoxicity can be mitigated, and provide insight into the molecular pathogenesis of spliceosome-associated diseases, such as retinitis pigmentosa.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:59:38.084.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thorsten Mosler
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-02 03:34:40	ID requested
1	2024-09-25 07:31:10	announced
⏵ 2	2024-10-22 06:59:38	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: USP39, splicing,ER

Ivan Dikic
contact affiliation	Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt; Frankfurt, Germany.
contact email	dikic@biochem2.uni-frankfurt.de
lab head
Thorsten Mosler
contact affiliation	Goethe University Clinics Frankfurt
contact email	thorstenmosler@googlemail.com
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/2024/09/PXD051146

PRIDE project URI

• PRIDE
  1. PXD051146
     1. Label: PRIDE project
     2. Name: Pathogenic Proteotoxicity of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy