Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy
| Autor: | Gun, West, Josef, Gullmets, Laura, Virtanen, Song-Ping, Li, Anni, Keinänen, Takeshi, Shimi, Monika, Mauermann, Tiina, Heliö, Maija, Kaartinen, Laura, Ollila, Johanna, Kuusisto, John E, Eriksson, Robert D, Goldman, Harald, Herrmann, Pekka, Taimen |
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| Rok vydání: | 2015 |
| Předmět: |
Cardiomyopathy
Dilated Cell Nucleus congenital hereditary and neonatal diseases and abnormalities animal structures integumentary system Green Fluorescent Proteins Fibroblasts Endoplasmic Reticulum Stress Lamin Type A Transfection Up-Regulation Protein Aggregates embryonic structures Mutation Humans Mutant Proteins Biomarkers Cells Cultured HeLa Cells Research Article |
| Zdroj: | Journal of cell science. 129(14) |
| ISSN: | 1477-9137 |
| Popis: | Mutation of the LMNA gene, encoding nuclear lamin A and lamin C (hereafter lamin A/C), is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here, we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild-type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A was significantly more dynamic. In in vitro association studies, p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole-genome expression analysis revealed an elevated unfolded protein response (UPR) in cells expressing p.S143P lamin A/C. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of cells expressing mutant lamin further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability. |
| Databáze: | OpenAIRE |
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