期刊
JOURNAL OF CELL SCIENCE
卷 129, 期 14, 页码 2732-2743出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.184150
关键词
Lamin; Dilated cardiomyopathy; Laminopathy; ER stress; UPR
类别
资金
- Sigrid Juselius Foundation (Sigrid Juseliuksen Saatio)
- Finnish Medical Foundation (Suomen Laaketieteen Saatio)
- Academy of Finland (Suomen Akatemia) [290160]
- Finnish Foundation for Cardiovascular Research (Sydantutkimussaatio)
- Paavo Nurmi Foundation
- Medicinska Understodsforeningen Liv och Halsa r.f.
- Svenska Kulturfonden
- Hospital District of Southwest Finland, Turku University Hospital ERVA funds
- Progeria Research Foundation
- National Institutes of Health - National Institute of General Medical Sciences
- German Research Foundation (Deutsche Forschungsgemeinschaft) [HE 1853]
- Academy of Finland (AKA) [290160, 290160] Funding Source: Academy of Finland (AKA)
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.
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