FHL1B Interacts with Lamin A/C and Emerin at the Nuclear Lamina and is Misregulated in Emery-Dreifuss Muscular Dystrophy

2016 ◽  
Vol 3 (4) ◽  
pp. 497-510 ◽  
Author(s):  
Esma Ziat ◽  
Kamel Mamchaoui ◽  
Maud Beuvin ◽  
Isabelle Nelson ◽  
Feriel Azibani ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Lamina ◽  
Lamin A

scholarly journals PCAF Involvement in Lamin A/C-HDAC2 Interplay during the Early Phase of Muscle Differentiation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1735
Author(s):  
Spartaco Santi ◽  
Vittoria Cenni ◽  
Cristina Capanni ◽  
Giovanna Lattanzi ◽  
Elisabetta Mattioli
Keyword(s):  
Muscular Dystrophy ◽  
Early Phase ◽  
Myogenic Differentiation ◽  
Nuclear Lamina ◽  
Muscle Differentiation ◽  
Lamin A ◽  
Histone Deacetylase 2 ◽  
Muscle Gene Expression ◽  
Muscle Gene ◽  
Human Muscle Cells

Lamin A/C has been implicated in the epigenetic regulation of muscle gene expression through dynamic interaction with chromatin domains and epigenetic enzymes. We previously showed that lamin A/C interacts with histone deacetylase 2 (HDAC2). In this study, we deepened the relevance and regulation of lamin A/C-HDAC2 interaction in human muscle cells. We present evidence that HDAC2 binding to lamin A/C is related to HDAC2 acetylation on lysine 75 and expression of p300-CBP associated factor (PCAF), an acetyltransferase known to acetylate HDAC2. Our findings show that lamin A and farnesylated prelamin A promote PCAF recruitment to the nuclear lamina and lamin A/C binding in human myoblasts committed to myogenic differentiation, while protein interaction is decreased in differentiating myotubes. Interestingly, PCAF translocation to the nuclear envelope, as well as lamin A/C-PCAF interaction, are reduced by transient expression of lamin A mutated forms causing Emery Dreifuss muscular dystrophy. Consistent with this observation, lamin A/C interaction with both PCAF and HDAC2 is significantly reduced in Emery–Dreifuss muscular dystrophy myoblasts. Overall, these results support the view that, by recruiting PCAF and HDAC2 in a molecular platform, lamin A/C might contribute to regulate their epigenetic activity required in the early phase of muscle differentiation.

scholarly journals The Genes, Proteins, and the Cell Biological Processes Underlying Emery-Dreifuss Muscular Dystrophy

2017 ◽  
Vol 6 (1) ◽  
pp. 14-18
Author(s):  
Elise Alexandra Kikis ◽  
Megan Elizabeth Mastey
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Autosomal Dominant ◽  
Nuclear Lamina ◽  
Autosomal Recessive Inheritance ◽  
Envelope Proteins ◽  
Lamin A ◽  
Dominant Form ◽  
Specific Effects ◽  
Autosomal Dominant Form

Emery-Dreifuss Muscular Dystrophy (EDMD) is a type of muscular dystrophy characterized by contractures, or shortening of muscles or joints in the elbows and Achilles tendons, muscle wasting and weakness as well as cardiomyopathy. There are two main forms of inherited EDMD, X-linked recessive and autosomal dominant. There is also a rarer form of autosomal recessive inheritance with only a few cases ever reported. The X-linked form of EDMD is caused by mutation of the STA gene that encodes the protein emerin, while the autosomal dominant form is caused by a missense mutation on the LMNA gene, which encodes lamin A/C proteins. Both emerin and lamin A/C are nuclear envelope proteins that interact with other proteins to create a connective network that attaches the nuclear lamina to the cytoskeleton. These nuclear envelope proteins interact via accessory proteins to chromatin and also thereby stimulate gene expression. The exact mechanism of how mutations in these genes lead to muscular dystrophy is not well understood. The “structural hypothesis,” states that the absence of these envelope proteins result in a weakened cell and would eventually end in nuclear disruption. The “gene regulatory hypothesis” states that emerin and lamin may be transcription factors whose absence results in tissue-specific effects. This review will addresses these hypotheses, describes what is known about the cell and molecular biology underlying EDMD and considers recent as advances in therapeutics.

The cell cycle dependent mislocalisation of emerin may contribute to the Emery-Dreifuss muscular dystrophy phenotype

2002 ◽  
Vol 115 (2) ◽  
pp. 341-354 ◽  
Author(s):  
Elizabeth A. L. Fairley ◽  
Andrew Riddell ◽  
Juliet A. Ellis ◽  
John Kendrick-Jones
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Nuclear Membrane ◽  
Transmembrane Domain ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Wild Type ◽  
Cycle Dependent ◽  
Mutant Forms

Emerin is the nuclear membrane protein defective in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). The majority of X-EDMD patients have no detectable emerin. However, there are cases that produce mutant forms of emerin, which can be used to study its function. Our previous studies have shown that the emerin mutants S54F, P183T, P183H, Del95-99, Del236-241 (identified in X-EDMD patients) are targeted to the nuclear membrane but to a lesser extent than wild-type emerin. In this paper, we have studied how the mislocalisation of these mutant emerins may affect nuclear functions associated with the cell cycle using flow cytometry and immunofluorescence microscopy. We have established that cells expressing the emerin mutant Del236-241 (a deletion in the transmembrane domain), which was mainly localised in the cytoplasm, exhibited an aberrant cell cycle length. Thereafter, by examining the intracellular localisation of endogenously expressed lamin A/C and exogenously expressed wild-type and mutant forms of emerin after a number of cell divisions, we determined that the mutant forms of emerin redistributed endogenous lamin A/C. The extent of lamin A/C redistribution correlated with the amount of EGFP-emerin that was mislocalised. The amount of EGFP-emerin mislocalized, in turn, was associated with alterations in the nuclear envelope morphology. The nuclear morphology and redistribution of lamin A/C was most severely affected in the cells expressing the emerin mutant Del236-241.It is believed that emerin is part of a novel nuclear protein complex consisting of the barrier-to-autointegration factor (BAF), the nuclear lamina, nuclear actin and other associated proteins. The data presented here show that lamin A/C localisation is dominantly directed by its interaction with certain emerin mutants and perhaps wild-type emerin as well. These results suggest that emerin links A-type lamins to the nuclear envelope and that the correct localisation of these nuclear proteins is important for maintaining cell cycle timing.

scholarly journals Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery–Dreifuss Muscular Dystrophy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 844 ◽  
Author(s):  
Anne T. Bertrand ◽  
Astrid Brull ◽  
Feriel Azibani ◽  
Louise Benarroch ◽  
Khadija Chikhaoui ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Striated Muscle ◽  
Congenital Muscular Dystrophy ◽  
In Silico Analysis ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Muscle Disorders ◽  
Severity Of The Disease ◽  
Type V ◽  
Tetramer Stability

LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery–Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype–phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes.

scholarly journals Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control

2021 ◽  
Vol 22 (13) ◽  
pp. 6669
Author(s):  
Byongsun Lee ◽  
Seungjae Lee ◽  
Younggwang Lee ◽  
Yongjin Park ◽  
Jaekyung Shim
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Membrane ◽  
Target Genes ◽  
Janus Kinase ◽  
C2c12 Cells ◽  
Specific Gene ◽  
Lamin A ◽  
Stat3 Signaling ◽  
Exact Function ◽  
Muscle Homeostasis

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). There has been accumulating evidence that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has still less revealing. Here, we have shown that emerin downregulates signal transducers and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus-kinase (JAK). Deletion mutation experiments showed that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacted directly and co-localized with STAT3 in the nuclear membrane. Emerin knockdown induced STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin by assembling with BAF and lamin A/C acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induced STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and could be a new therapeutic target for treatment.

scholarly journals Reduced Lamin A/C does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2383
Author(s):  
Francesco Roncato ◽  
Ofer Regev ◽  
Sara W. Feigelson ◽  
Sandeep Kumar Yadav ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Lung Metastasis ◽  
Metastatic Cancer ◽  
Nuclear Lamina ◽  
Transendothelial Migration ◽  
Soft Agar ◽  
Lamin A ◽  
And Migration

The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.

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