PXD041509-2

PXD041509 is an original dataset announced via ProteomeXchange.

Title	The Pathogenic Impact of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy
Description	RNA splicing and the ubiquitin system allow the functional proteome to adapt in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here we show that the deregulation of the spliceosome B complex caused by USP39 deficiency leads to a novel splicing profile characterized by the use of cryptic 5′splice sites. Importantly, disruptive variants evade mRNA surveillance pathways and are translated into topologically incorrect proteins. These cryptic isoforms disrupt proteostasis and activate the unfolded protein response, causing ER stress-induced cell death. Human cells respond to this proteotoxicity by enhancing ubiquitin-mediated proteolysis and ER-phagy. Our findings show how cell death triggered by cryptic splicing can be mitigated, and provide insight into the molecular pathogenesis of diseases such as retinitis pigmentosa.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:59:43.547.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marina Hoffmann
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitination signature dipeptidyl lysine
Instrument	Q Exactive HF; Orbitrap Fusion Lumos; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-13 02:58:50	ID requested
1	2024-09-26 11:50:33	announced
⏵ 2	2024-10-22 06:59:43	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: USP39, ER-phagy,RNA splicing, LC-MS/MS

Ivan Dikic
contact affiliation	Institute of Biochemistry II, Goethe University Medical Faculty
contact email	dikic@biochem2.uni-frankfurt.de
lab head
Marina Hoffmann
contact affiliation	institute of biochemistry 2 (IBC2)
contact email	hoffmann@med.uni-frankfurt.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041509
     1. Label: PRIDE project
     2. Name: The Pathogenic Impact of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy