Deleterious assembly of mutant p.S143P lamin A/C causes ER stress in familial dilated cardiomyopathy
| Autor: | Gun West, Anni Keinänen, Laura Virtanen, Pekka Taimen, Robert D. Goldman, Maija Kaartinen, Takeshi Shimi, Song Ping Li, Harald Herrmann, Laura Ollila, Josef Gullmets, Monika Mauermann, Tiina Heliö, Johanna Kuusisto, John E. Eriksson |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities animal structures integumentary system Endoplasmic reticulum Laminopathy Cell Biology Tunicamycin Biology medicine.disease Molecular biology LMNA 03 medical and health sciences Cell nucleus chemistry.chemical_compound 030104 developmental biology medicine.anatomical_structure chemistry embryonic structures Unfolded protein response medicine Nuclear lamina Lamin |
| Zdroj: | Journal of Cell Science. |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.184150 |
| 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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