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Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway
Journal article   Open access   Peer reviewed

Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway

George Dialynas, Om K Shrestha, Jessica M Ponce, Monika Zwerger, Dylan A Thiemann, Grant H Young, Steven A Moore, Liping Yu, Jan Lammerding and Lori L Wallrath
PLoS genetics, Vol.11(5), pp.e1005231-e1005231
05/2015
DOI: 10.1371/journal.pgen.1005231
PMCID: PMC4440730
PMID: 25996830
url
https://doi.org/10.1371/journal.pgen.1005231View
Published (Version of record) Open Access

Abstract

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.
 Oxidative Stress Sequestosome-1 Protein Homeostasis Muscle, Skeletal - metabolism Gene Expression Profiling Intracellular Signaling Peptides and Proteins - metabolism Muscular Dystrophies - genetics Nuclear Lamina - metabolism Nuclear Lamina - genetics NF-E2-Related Factor 2 - genetics Intracellular Signaling Peptides and Proteins - genetics Kelch-Like ECH-Associated Protein 1 Drosophila - genetics Signal Transduction Gene Expression Regulation Lamin Type A - metabolism Protein Folding Animals NF-E2-Related Factor 2 - metabolism Adaptor Proteins, Signal Transducing - genetics Lamin Type A - genetics Protein Conformation Drosophila - metabolism Mutation Adaptor Proteins, Signal Transducing - metabolism Cell Nucleus

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