PXD033937 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Proteasome dysfunction leads to enhanced autophagy mediated degradation of mutant lamin A/C |
Description | Lamin A/C are nuclear intermediate filament proteins that form a proteinaceous meshwork called lamina beneath the inner nuclear membrane. Mutations in the LMNA gene encoding lamin A/C cause a heterogenous group of inherited degenerative diseases known as laminopathies. Previous studies have revealed altered cell signaling pathways in lamin mutant patient cells, but little is known about the fate of mutant lamin A/C within the cells. Here, we analyzed the turnover of lamin A/C in cells derived from a dilated cardiomyopathy patient with a heterozygous p.S143P mutation in LMNA. We found that transcriptional activation and mRNA levels of LMNA are increased in the primary patient fibroblasts, but that the lamin A/C protein levels remain equal in control and patient cells because of a meticulous interplay between autophagy and the ubiquitin-proteasome system (UPS). Both endogenous and ectopic expression of p.S143P lamin A/C cause significantly reduced activity of UPS and accumulation of K48-ubiquitin chains in the nucleus. Furthermore, K48-ubiquitinated lamin A/C is degraded by compensatory enhanced autophagy, as shown by increased autophagosome formation and binding of lamin A/C to microtubule-associated protein 1A/1B-light chain 3. Finally, a chaperone 4-PBA augmented protein degradation by restoring UPS activity as well as autophagy in the patient cells. In summary, our results suggest that the p.S143P mutant lamin A/C has overloading and deleterious effects on protein degradation machinery and pharmacological interventions with compounds enhancing protein degradation may be beneficial for cell homeostasis. |
HostingRepository | PRIDE |
AnnounceDate | 2022-09-07 |
AnnouncementXML | Submission_2022-09-07_03:36:41.985.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Gun West |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-05-17 08:23:55 | ID requested | |
⏵ 1 | 2022-09-07 03:36:42 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: lamin A/C, autophagy, disease mutations, ubiquitin, degradation, ubiquitin-proteasome-system |
Contact List
Pekka Taimen |
contact affiliation | Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital Medisiina D, 5th floor Kiinamyllynkatu 10 20520 Turku Finland |
contact email | pepeta@utu.fi |
lab head | |
Gun West |
contact affiliation | University of Turku |
contact email | gunwes@utu.fi |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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[ - ]
- PRIDE
- PXD033937
- Label: PRIDE project
- Name: Proteasome dysfunction leads to enhanced autophagy mediated degradation of mutant lamin A/C