Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Pande, Shruti; Ghosh, Debasish Kumar

doi:10.1096/fj.202300878r

Cited by 2 publications

(2 citation statements)

References 255 publications

(408 reference statements)

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“…Another example is AMPK, a master regulator of cellular energy metabolism, which was dysregulated in our Q353 K data set as well as in human muscle tissue for the G449 V-linked laminopathy . These processes and pathways are not mutually exclusive with interplay between most . For example, mutations that aggregate or perturb ER homeostasis could trigger proteasomal, apoptotic, and/or autophagic pathways for which there is crosstalk .…”

Section: Discussionmentioning

confidence: 99%

“…76 These processes and pathways are not mutually exclusive with interplay between most. 77 For example, mutations that aggregate or perturb ER homeostasis could trigger proteasomal, apoptotic, and/or autophagic pathways for which there is crosstalk. 78 Scaffolding proteins are another example that can have numerous effects including contractility, signaling, and apoptosis when dysfunctional.…”

Section: Mitochondrial Dysfunction and Redox Homeostasismentioning

confidence: 99%

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Global Proteomic Analysis Reveals Alterations in Differentially Expressed Proteins between Cardiopathic Lamin A/C Mutations

Anderson,

Brown,

North

et al. 2024

J. Proteome Res.

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Lamin A/C (LMNA) is an important component of nuclear lamina. Mutations cause arrhythmia, heart failure, and sudden cardiac death. While LMNA-associated cardiomyopathy typically has an aggressive course that responds poorly to conventional heart failure therapies, there is variability in severity and age of penetrance between and even within specific mutations, which is poorly understood at the cellular level. Further, this heterogeneity has not previously been captured to mimic the heterozygous state, nor have the hundreds of clinical LMNA mutations been represented. Herein, we have overexpressed cardiopathic LMNA variants in HEK cells and utilized state-ofthe-art quantitative proteomics to compare the global proteomic profiles of (1) aggregating Q353 K alone, (2) Q353 K coexpressed with WT, (3) aggregating N195 K coexpressed with WT, and (4) nonaggregating E317 K coexpressed with WT to help capture some of the heterogeneity between mutations. We analyzed each data set to obtain the differentially expressed proteins (DEPs) and applied gene ontology (GO) and KEGG pathway analyses. We found a range of 162 to 324 DEPs from over 6000 total protein IDs with differences in GO terms, KEGG pathways, and DEPs important in cardiac function, further highlighting the complexity of cardiac laminopathies. Pathways disrupted by LMNA mutations were validated with redox, autophagy, and apoptosis functional assays in both HEK 293 cells and in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) for LMNA N195 K. These proteomic profiles expand our repertoire for mutation-specific downstream cellular effects that may become useful as druggable targets for personalized medicine approach for cardiac laminopathies.

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Section: Discussionmentioning

confidence: 99%

Section: Mitochondrial Dysfunction and Redox Homeostasismentioning

confidence: 99%

Global Proteomic Analysis Reveals Alterations in Differentially Expressed Proteins between Cardiopathic Lamin A/C Mutations

Anderson,

Brown,

North

et al. 2024

J. Proteome Res.

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The Dual Roles of Lamin A/C in Mechanosensation to Compressive Force

Groeger,

Wang,

Ruf

et al. 2023

Preprint

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Cellular mechanosensation is a complex physiological process coupling alterations in the external environment and cellular behaviors. Over the past decade, the role of the nucleus in mechanosensation has gained increasing attention. Our research found that lamin A/C, a component of the nuclear envelope, plays a dual role in the mechanosensation of macrophages in response to compressive force. Our findings indicated that hydrostatic compressive force downregulated lamin A/C protein via the cytoskeleton. Consequently, this lamin A/C deficiency enhanced compressive-force-induced inflammatory cytokines secretion and proliferative impairment. Unexpectedly, lamin A deficiency also inhibits compressive force-induced DNA damage and interferon regulatory factor 4 (IRF4) up-regulation. Our findings suggest that lamin A/C is involved in multiple mechanosensation mechanisms. Mechanistically, lamin A/C deficiency augments nuclear permeability, facilitates the activation of yes-associated protein 1 (YAP1) and promotes force-induced nuclear translocation of YAP1. These mechanisms have been validated to favor mechanosensation. Conversely, we also found that lamin A/C deficiency led to detachment of components of linker of nucleoskeleton and cytoskeleton (LINC) complex, which impeded intracellular mechanotransmission. In summary, lamin A/C can promote some responses of macrophages to mechanical compression but inhibits others. It is involved in two distinct mechanisms: enhancing nuclear permeability to transcription factors and impairing mechanotransmission by disrupting the LINC complex's connection to the nucleus.

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Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Cited by 2 publications

References 255 publications

Global Proteomic Analysis Reveals Alterations in Differentially Expressed Proteins between Cardiopathic Lamin A/C Mutations

Global Proteomic Analysis Reveals Alterations in Differentially Expressed Proteins between Cardiopathic Lamin A/C Mutations

The Dual Roles of Lamin A/C in Mechanosensation to Compressive Force

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