A heterozygous p.S143P mutation in LMNA associates with proteasome dysfunction and enhanced autophagy-mediated degradation of mutant lamins A and C



: West Gun, Turunen Minttu, Aalto Anna, Virtanen Laura, Li Song-Ping, Heliö Tiina, Meinander Annika, Taimen Pekka

Publisher: FRONTIERS MEDIA SA

: 2022

: Frontiers in cell and developmental biology

: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY

: FRONT CELL DEV BIOL

:  932983

: 10

: 15

: 2296-634X

DOI: https://doi.org/10.3389/fcell.2022.932983

: https://www.frontiersin.org/articles/10.3389/fcell.2022.932983/full

: https://research.utu.fi/converis/portal/detail/Publication/176652676


Lamins A and C are nuclear intermediate filament proteins that form a proteinaceous meshwork called lamina beneath the inner nuclear membrane. Mutations in the LMNA gene encoding lamins A and 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 lamins A and C within the cells. Here, we analyzed the turnover of lamins A and 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 the protein levels of lamins A and C 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 lamins A and C cause significantly reduced activity of UPS and an accumulation of K48-ubiquitin chains in the nucleus. Furthermore, K48-ubiquitinated lamins A and C are degraded by compensatory enhanced autophagy, as shown by increased autophagosome formation and binding of lamins A and C to microtubule-associated protein 1A/1B-light chain 3. Finally, 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 lamins A and C have overloading and deleterious effects on protein degradation machinery and pharmacological interventions with compounds enhancing protein degradation may be beneficial for cell homeostasis.

Last updated on 2024-26-11 at 18:52