RanGTPase regulates the interaction between the inner nuclear membrane proteins, Samp1 and Emerin

Vijayaraghavan, Balaje; Figueroa, Ricardo; Bergqvist, Cecilia; Gupta, Amit J.; Sousa, Paulo; Hallberg, Einar

doi:10.1016/j.bbamem.2018.03.001

Cited by 8 publications

(10 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Emerin has at least two modes of self-association with the potential to form networks or filaments (Berk et al, 2014; Herrada et al, 2015; Samson et al, 2017). Other partners include nucleo/cytoskeletal proteins (e.g., F-actin, myosin 1c, tubulin), nuclear membrane proteins (e.g., LAP1, Samp1) and transcriptional regulators such as HDAC3, b-catenin and Lmo7 (Holaska et al, 2006; Berk et al, 2013b; Shin et al, 2013; Barton et al, 2015; Vijayaraghavan et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Dharmaraj

Guan

Liu

et al. 2019

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Emerin ( EMD ) and barrier to autointegration factor 1 ( BANF1 ) each bind A-type lamins ( LMNA ) as fundamental components of nuclear lamina structure. Mutations in LMNA , EMD and BANF1 are genetically linked to many tissue-specific disorders including Emery-Dreifuss muscular dystrophy and cardiomyopathy ( LMNA , EMD ), lipodystrophy, insulin resistance and type 2 diabetes ( LMNA ) and progeria ( LMNA , BANF1 ). To explore human genetic variation in these genes, we analyzed EMD and BANF1 alleles in the Exome Aggregation Consortium (ExAC) cohort of 60,706 unrelated individuals. We identified 13 rare heterozygous BANF1 missense variants (p.T2S, p.H7Y, p.D9N, p.S22R, p.G25E, p.D55N, p.D57Y, p.L63P, p.N70T, p.K72R, p.R75W, p.R75Q, p.G79R), and one homozygous variant (p.D9H). Several variants are known (p.G25E) or predicted (e.g., p.D9H, p.D9N, p.L63P) to perturb BANF1 and warrant further study. Analysis of EMD revealed two previously identified variants associated with adult-onset cardiomyopathy (p.K37del, p.E35K) and one deemed ‘benign’ in an Emery-Dreifuss patient (p.D149H). Interestingly p.D149H was the most frequent emerin variant in ExAC, identified in 58 individuals (overall allele frequency 0.06645%), of whom 55 were East Asian (allele frequency 0.8297%). Furthermore, p.D149H associated with four ‘healthy’ traits: reduced triglycerides (-0.336; p = 0.0368), reduced waist circumference (-0.321; p = 0.0486), reduced cholesterol ( - 0.572; p = 0.000346) and reduced LDL cholesterol (-0.599; p = 0.000272). These traits are distinct from LMNA -associated metabolic disorders and provide the first insight that emerin influences metabolism. We also identified one novel in-frame deletion (p.F39del) and 62 novel emerin missense variants, many of which were relatively frequent and potentially disruptive including p.N91S and p.S143F (∼0.041% and ∼0.034% of non-Finnish Europeans, respectively), p.G156S (∼0.39% of Africans), p.R204G (∼0.18% of Latinx), p.R207P (∼0.08% of South Asians) and p.R221L (∼0.15% of Latinx). Many novel BANF1 variants are predicted to disrupt dimerization or binding to DNA, histones, emerin or A-type lamins. Many novel emerin variants are predicted to disrupt emerin filament dynamics or binding to BANF1, HDAC3, A-type lamins or other partners. These new human variants provide a foundational resource for future studies to test the molecular mechanisms of BANF1 and emerin function, and to understand the link between emerin variant p.D149H and a ‘healthy’ lipid profile.

show abstract

Section: Introductionmentioning

confidence: 99%

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Dharmaraj

Guan

Liu

et al. 2019

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…In fact, Samp1 directs localization of gamma-tubulin, which is a major component of centrosomal complexes [ 22 ]. Furthermore, Samp1 interacts with LINC proteins SUN2, SUN1, emerin, and A-type lamins [ 23 , 24 , 25 ] and interferes with nuclear movement [ 26 ]. Samp1 is required for muscle cell differentiation, which was demonstrated in mouse myoblasts and human induced pluripotent stem cells [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy

Mattioli

Columbaro

Jafferali

et al. 2018

Cells

Self Cite

View full text Add to dashboard Cite

LMNA linked-Emery-Dreifuss muscular dystrophy (EDMD2) is a rare disease characterized by muscle weakness, muscle wasting, and cardiomyopathy with conduction defects. The mutated protein lamin A/C binds several nuclear envelope components including the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the inner nuclear membrane protein Samp1 (Spindle Associated Membrane Protein 1). Considering that Samp1 is upregulated during muscle cell differentiation and it is involved in nuclear movement, we hypothesized that it could be part of the protein platform formed by LINC proteins and prelamin A at the myotube nuclear envelope and, as previously demonstrated for those proteins, could be affected in EDMD2. Our results show that Samp1 is uniformly distributed at the nuclear periphery of normal human myotubes and committed myoblasts, but its anchorage at the nuclear poles is related to the presence of farnesylated prelamin A and it is disrupted by the loss of prelamin A farnesylation. Moreover, Samp1 is absent from the nuclear poles in EDMD2 myotubes, which shows that LMNA mutations associated with muscular dystrophy, due to reduced prelamin A levels in muscle cell nuclei, impair Samp1 anchorage. Conversely, SUN1 pathogenetic mutations do not alter Samp1 localization in myotubes, which suggests that Samp1 lies upstream of SUN1 in nuclear envelope protein complexes. The hypothesis that Samp1 is part of the protein platform that regulates microtubule nucleation from the myotube nuclear envelope in concert with pericentrin and LINC components warrants future investigation. As a whole, our data identify Samp1 as a new contributor to EDMD2 pathogenesis and our data are relevant to the understanding of nuclear clustering occurring in laminopathic muscle.

show abstract

“…Emerin interacts with many proteins during interphase [34,35], among which LUMA [41], HDAC3 [42], Btf [43], GCL [44], actin [45], Lmo7 [46], NET25 [47], and β-catenin [48] appear most crucial in the context of the structure of the cell nucleus, nuclear lamina, and chromatin. Emerin interacts with Samp1 (NET5) [92] and is indirectly involved in positioning of two chromosomes in the cell nucleus [93], but previous studies have also found no changes in location of chromosome territories in emerin-null patients [94].…”

Section: Discussionmentioning

confidence: 99%

Emerin Is Required for Proper Nucleus Reassembly after Mitosis: Implications for New Pathogenetic Mechanisms for Laminopathies Detected in EDMD1 Patients

Dubińska–Magiera

Kozioł

Machowska

et al. 2019

Cells

View full text Add to dashboard Cite

Emerin is an essential LEM (LAP2, Emerin, MAN1) domain protein in metazoans and an integral membrane protein associated with inner and outer nuclear membranes. Mutations in the human EMD gene coding for emerin result in the rare genetic disorder: Emery–Dreifuss muscular dystrophy type 1 (EDMD1). This disease belongs to a broader group called laminopathies—a heterogeneous group of rare genetic disorders affecting tissues of mesodermal origin. EDMD1 phenotype is characterized by progressive muscle wasting, contractures of the elbow and Achilles tendons, and cardiac conduction defects. Emerin is involved in many cellular and intranuclear processes through interactions with several partners: lamins; barrier-to-autointegration factor (BAF), β-catenin, actin, and tubulin. Our study demonstrates the presence of the emerin fraction which associates with mitotic spindle microtubules and centrosomes during mitosis and colocalizes during early mitosis with lamin A/C, BAF, and membranes at the mitotic spindle. Transfection studies with cells expressing EGFP-emerin protein demonstrate that the emerin fusion protein fraction also localizes to centrosomes and mitotic spindle microtubules during mitosis. Transient expression of emerin deletion mutants revealed that the resulting phenotypes vary and are mutant dependent. The most frequent phenotypes include aberrant nuclear shape, tubulin network mislocalization, aberrant mitosis, and mislocalization of centrosomes. Emerin deletion mutants demonstrated different chromatin binding capacities in an in vitro nuclear assembly assay and chromatin-binding properties correlated with the strength of phenotypic alteration in transfected cells. Aberrant tubulin staining and microtubule network phenotype appearance depended on the presence of the tubulin binding region in the expressed deletion mutants. We believe that the association with tubulin might help to “deliver” emerin and associated membranes to decondensing chromatin. Preliminary analyses of cells from Polish patients with EDMD1 revealed that for several mutations thought to be null for emerin protein, a truncated emerin protein was present. We infer that the EDMD1 phenotype may be strengthened by the toxicity of truncated emerin expressed in patients with certain nonsense mutations in EMD.

show abstract

RanGTPase regulates the interaction between the inner nuclear membrane proteins, Samp1 and Emerin

Cited by 8 publications

References 45 publications

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Rare BANF1 Alleles and Relatively Frequent EMD Alleles Including ‘Healthy Lipid’ Emerin p.D149H in the ExAC Cohort

Samp1 Mislocalization in Emery-Dreifuss Muscular Dystrophy

Emerin Is Required for Proper Nucleus Reassembly after Mitosis: Implications for New Pathogenetic Mechanisms for Laminopathies Detected in EDMD1 Patients

Contact Info

Product

Resources

About