Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway.
Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway.
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DOI：
10.1371/journal.pgen.1005231
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发表时间：
2015-05
期刊：
影响因子：
4.5
通讯作者：
Wallrath LL
中科院分区：
文献类型：
--
作者：
Dialynas G;Shrestha OK;Ponce JM;Zwerger M;Thiemann DA;Young GH;Moore SA;Yu L;Lammerding J;Wallrath LL
Mutations in the human LMNA gene cause muscular dystrophy by mechanisms that are incompletely understood. The LMNA gene encodes A-type lamins, intermediate filaments that form a network underlying the inner nuclear membrane, providing structural support for the nucleus and organizing the genome. To better understand the pathogenesis caused by mutant lamins, we performed a structural and functional analysis on LMNA missense mutations identified in muscular dystrophy patients. These mutations perturb the tertiary structure of the conserved A-type lamin Ig-fold domain. To identify the effects of these structural perturbations on lamin function, we modeled these mutations in Drosophila Lamin C and expressed the mutant lamins in muscle. We found that the structural perturbations had minimal dominant effects on nuclear stiffness, suggesting that the muscle pathology was not accompanied by major structural disruption of the peripheral nuclear lamina. However, subtle alterations in the lamina network and subnuclear reorganization of lamins remain possible. Affected muscles had cytoplasmic aggregation of lamins and additional nuclear envelope proteins. Transcription profiling revealed upregulation of many Nrf2 target genes. Nrf2 is normally sequestered in the cytoplasm by Keap-1. Under oxidative stress Nrf2 dissociates from Keap-1, translocates into the nucleus, and activates gene expression. Unexpectedly, biochemical analyses revealed high levels of reducing agents, indicative of reductive stress. The accumulation of cytoplasmic lamin aggregates correlated with elevated levels of the autophagy adaptor p62/SQSTM1, which also binds Keap-1, abrogating Nrf2 cytoplasmic sequestration, allowing Nrf2 nuclear translocation and target gene activation. Elevated p62/SQSTM1 and nuclear enrichment of Nrf2 were identified in muscle biopsies from the corresponding muscular dystrophy patients, validating the disease relevance of our Drosophila model. Thus, novel connections were made between mutant lamins and the Nrf2 signaling pathway, suggesting new avenues of therapeutic intervention that include regulation of protein folding and metabolism, as well as maintenance of redox homoeostasis. Mutations in the human LMNA gene cause muscular dystrophy that is often accompanied by heart disease. The LMNA gene makes proteins that form a network on the inner side of the nuclear envelope, a structure that reinforces the cell nucleus. How mutations in the LMNA gene cause muscle disease is not well understood. Our studies provide evidence that LMNA mutations activate an intracellular signaling pathway and alter the redox homeostasis of muscle tissue. Thus, our results suggest that blocking the signaling pathway and maintaining the oxidative state of the diseased muscle are potential therapies for muscular dystrophy patients with LMNA mutations.
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