PXD033937

PXD033937 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-17 08:23:55	ID requested
⏵ 1	2022-09-07 03:36:42	announced

Dataset with its publication pending

submitter keyword: lamin A/C, autophagy, disease mutations, ubiquitin, degradation, ubiquitin-proteasome-system

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

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PRIDE project URI

• PRIDE
  1. PXD033937
     1. Label: PRIDE project
     2. Name: Proteasome dysfunction leads to enhanced autophagy mediated degradation of mutant lamin A/C