PXD009803

PXD009803 is an original dataset announced via ProteomeXchange.

Title	The ubiquitin ligase UBR5 suppresses proteostasis collapse in immortal pluripotent stem cells and Huntington’s disease models
Description	Pluripotent stem cells undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome, a capacity that demands a highly induced proteostasis network. As such, induced pluripotent stem cells (iPSCs) suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington’s disease (HD). Here we show that proteasome activity determines HTT levels, preventing the accumulation of polyQ-expanded aggregates in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit intrinsic high levels of UBR5, an E3 ubiquitin ligase that we find required for proteasomal degradation of both normal and mutant HTT. When UBR5 fails to monitor HTT proteostasis, the concomitant up-regulation of HTT expression particularly results in polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens protein aggregation and neurotoxicity in polyQ-expanded invertebrate models. Notably, ectopic expression of UBR5 is sufficient to induce polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD cell models. However, UBR5 is dispensable for the proteostasis of other aggregation-prone proteins linked with Machado-Joseph disease or amyotrophic lateral sclerosis in iPSCs. Besides its role in HTT regulation, we find that intrinsic high levels of UBR5 also determine the global proteostatic ability of iPSCs preventing aggresome formation, suggesting a role in the control of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a central component of super-vigilant proteostasis of iPSCs with the potential to correct proteostatic deficiencies in HD.
HostingRepository	PRIDE
AnnounceDate	2018-06-14
AnnouncementXML	Submission_2018-06-14_08:27:49.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Vilchez
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitination signature dipeptidyl lysine
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2018-05-16 08:14:44	ID requested
⏵ 1	2018-06-14 08:27:49	announced

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: Human cells (293), HTT

David Vilchez
contact affiliation	Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne Joseph Stelzmann Strasse 26 50931 Cologne, Germany Phone number: +49 22147884172 Fax number: +49 221 478 84045 E-mail: dvilchez@uni-koeln.de
contact email	dvilchez@uni-koeln.de
lab head
David Vilchez
contact affiliation	University of Cologne
contact email	dvilchez@uni-koeln.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD009803
     1. Label: PRIDE project
     2. Name: The ubiquitin ligase UBR5 suppresses proteostasis collapse in immortal pluripotent stem cells and Huntington’s disease models