Phosphorylation of Lamin A/C at serine 22 modulates Na
            <sub>v</sub>
            1.5 function

Olaopa, Michael; Ai, Tomohiko; Chao, Bo; Xiao, Xiangshu; Vatta, Matteo; Habecker, Beth A.

doi:10.14814/phy2.15121

Cited by 4 publications

(5 citation statements)

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“…Some kinases, such as Cdk1 and PCK, can also phosphorylate lamins in the interphase; a few sites are reported as mitotic sites, such as Ser22 and Ser392, but with a much lower rate than mitosis. A new study reported that Ser22 phosphorylation of lamin A/C could modulate the cardiac sodium channel, associated with cardiac conduction disease ( Olaopa et al, 2021 ). Another research demonstrated that lamin C was more strongly phosphorylated at Ser22 than lamin A in interphase fibroblasts ( Kolb et al, 2011 ); the reason might be that lamin C was easy to be touched by kinase due to its proximity to the nuclear interior ( Kolb et al, 2011 ).…”

Section: Phosphorylation: Multifunctional Post-translational Modifica...mentioning

confidence: 99%

Post-Translational Modification of Lamins: Mechanisms and Functions

Zheng

Jin

Zhou

2022

Front. Cell Dev. Biol.

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Lamins are the ancient type V intermediate filament proteins contributing to diverse biological functions, such as the maintenance of nuclear morphology, stabilization of chromatin architecture, regulation of cell cycle progression, regulation of spatial-temporal gene expressions, and transduction of mechano-signaling. Deregulation of lamins is associated with abnormal nuclear morphology and chromatin disorganization, leading to a variety of diseases such as laminopathy and premature aging, and might also play a role in cancer. Accumulating evidence indicates that lamins are functionally regulated by post-translational modifications (PTMs) including farnesylation, phosphorylation, acetylation, SUMOylation, methylation, ubiquitination, and O-GlcNAcylation that affect protein stabilization and the association with chromatin or associated proteins. The mechanisms by which these PTMs are modified and the relevant functionality become increasingly appreciated as understanding of these changes provides new insights into the molecular mechanisms underlying the laminopathies concerned and novel strategies for the management. In this review, we discussed a range of lamin PTMs and their roles in both physiological and pathological processes, as well as potential therapeutic strategies by targeting lamin PTMs.

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Section: Phosphorylation: Multifunctional Post-translational Modifica...mentioning

confidence: 99%

Post-Translational Modification of Lamins: Mechanisms and Functions

Zheng

Jin

Zhou

2022

Front. Cell Dev. Biol.

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“…Genes encoding for eukaryotic translation initiation and tRNA charging were also perturbed in the mutant scenario suggesting alteration in protein production machinery and kinetics. Moreover, genes associated with cell–cell adhesion, cell–matrix adhesion, and voltage gated ion channels were found to be dysregulated which were also previously reported to cause DCM presumably through disturbed mechanotransduction phenomenon (El‐Battrawy et al., 2018; Asatryan, 2019; Molina‐Navarro et al., 2013; Olaopa et al., 2021). We further validated by qRTPCR the differential expression of genes from the interleukin‐ and chemokine‐mediated signaling pathways, such as NOS2 (nitric oxide synthase 2), FAS (TNF receptor superfamily member 6), CXCL5 (chemokine with C‐X‐C motif ligand 5), IFI206 (interferon activated gene 206), MPEG1 (macrophage expressed gene 1), IL6 (interleukin 6), TNFRSF9 (tumor necrosis factor receptor superfamily, member 9), CXCL1 (chemokine of C‐X‐C motif ligand 1), CCL11 (chemokine of C‐C motif ligand 11) (Figure 4a).…”

Section: Resultsmentioning

confidence: 64%

Lamin A K97E leads to NF‐κB‐mediated dysfunction of inflammatory responses in dilated cardiomyopathy

Sengupta,

Sengupta

2024

Biology of the Cell

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Background InformationLamins are type V intermediate filament proteins underlying the inner nuclear membrane which provide structural rigidity to the nucleus, tether the chromosomes, maintain nuclear homeostasis, and remain dynamically associated with developmentally regulated regions of the genome. A large number of mutations particularly in the LMNA gene encoding lamin A/C results in a wide array of human diseases, collectively termed as laminopathies. Dilated Cardiomyopathy (DCM) is one such laminopathic cardiovascular disease which is associated with systolic dysfunction of left or both ventricles leading to cardiac arrhythmia which ultimately culminates into myocardial infarction.ResultsIn this work, we have unraveled the epigenetic landscape to address the regulation of gene expression in mouse myoblast cell line in the context of the missense mutation LMNA 289A<G (Lys97Glu) that is found in DCM‐afflicted patient with severe symptoms. Significant changes in H3‐specific epigenetic modifications indicated a dysregulation in transcription machinery which was investigated by RNA sequencing analysis. The major pathways involved in IL‐17 signaling, cellular response to interferon‐beta and gamma, cytokine production, and related pathways are found to be downregulated. Analysis of the promoter sequences of the genes in the abovementioned pathways led us to the master regulator NF‐κB and its regulatory network.ConclusionsWe report here for the first time that there is a significant downregulation of the NF‐κB pathway, which has been implicated in cardio‐protection elsewhere.SignificanceThis provides a new pathophysiological explanation that correlates an LMNA mutation and dilated cardiomyopathy.

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“…Reduced stiffness dephosphorylates lamin-A/C at Ser22, which mediates lamina signaling (Buxboim et al, 2014;Virtanen et al, 2023) and differential expression of lamin-A/C as an extracellular matrix-dependent mechanosensor protein has also been suggested (Ovsiannikova et al, 2021;Urciuoli et al, 2021). More recently, phosphorylation of lamin-A/C at Ser22 modulates voltage-gated Na V 1.5 channel activity (Olaopa et al, 2021). These results may provide the potent role of lamin on the transitional pattern of adhesion to suspension.…”

Section: Various Modulating Factors and Effector Signals On Lamin-a/c...mentioning

confidence: 97%

Overview of cellular homeostasis-associated nuclear envelope lamins and associated input signals

Kim

Lee

Hong

2023

Front. Cell Dev. Biol.

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With the discovery of the role of the nuclear envelope protein lamin in human genetic diseases, further diverse roles of lamins have been elucidated. The roles of lamins have been addressed in cellular homeostasis including gene regulation, cell cycle, cellular senescence, adipogenesis, bone remodeling as well as modulation of cancer biology. Features of laminopathies line with oxidative stress-associated cellular senescence, differentiation, and longevity and share with downstream of aging-oxidative stress. Thus, in this review, we highlighted various roles of lamin as key molecule of nuclear maintenance, specially lamin-A/C, and mutated LMNA gene clearly reveal aging-related genetic phenotypes, such as enhanced differentiation, adipogenesis, and osteoporosis. The modulatory roles of lamin-A/C in stem cell differentiation, skin, cardiac regulation, and oncology have also been elucidated. In addition to recent advances in laminopathies, we highlighted for the first kinase-dependent nuclear lamin biology and recently developed modulatory mechanisms or effector signals of lamin regulation. Advanced knowledge of the lamin-A/C proteins as diverse signaling modulators might be biological key to unlocking the complex signaling of aging-related human diseases and homeostasis in cellular process.

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Phosphorylation of Lamin A/C at serine 22 modulates Na _v 1.5 function

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 4 publications

References 49 publications

Post-Translational Modification of Lamins: Mechanisms and Functions

Post-Translational Modification of Lamins: Mechanisms and Functions

Lamin A K97E leads to NF‐κB‐mediated dysfunction of inflammatory responses in dilated cardiomyopathy

Overview of cellular homeostasis-associated nuclear envelope lamins and associated input signals

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Phosphorylation of Lamin A/C at serine 22 modulates Na v 1.5 function

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 4 publications

References 49 publications

Post-Translational Modification of Lamins: Mechanisms and Functions

Post-Translational Modification of Lamins: Mechanisms and Functions

Lamin A K97E leads to NF‐κB‐mediated dysfunction of inflammatory responses in dilated cardiomyopathy

Overview of cellular homeostasis-associated nuclear envelope lamins and associated input signals

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Product

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Phosphorylation of Lamin A/C at serine 22 modulates Na _v 1.5 function