Nucleoporins in cardiovascular disease

Burdine, Ryan D.; Preston, Claudia C.; Leonard, Riley J; Bradley, Tyler A.; Faustino, Randolph S.

doi:10.1016/j.yjmcc.2020.02.010

Cited by 15 publications

(12 citation statements)

References 150 publications

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“…Inner ring complex of the NPC was constituted by Nup93, Nup205, Nup188, and Nup155 (ref. 38 ). Inner ring components of the NPC were essential for nuclear assembly and nuclear envelope formation 39 , 40 .…”

Section: Resultsmentioning

confidence: 99%

Biallelic loss of function NEK3 mutations deacetylate α-tubulin and downregulate NUP205 that predispose individuals to cilia-related abnormal cardiac left–right patterning

Zhang¹,

Chen²,

Zeng³

et al. 2020

Cell Death Dis

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Defective left–right (LR) organization involving abnormalities in cilia ultrastructure causes laterality disorders including situs inversus (SI) and heterotaxy (Htx) with the prevalence approximately 1/10,000 births. In this study, we describe two unrelated family trios with abnormal cardiac LR patterning. Through whole-exome sequencing (WES), we identified compound heterozygous mutations (c.805-1G >C; p. Ile269GlnfsTer8/c.1117dupA; p.Thr373AsnfsTer19) (c.29T>C; p.Ile10Thr/c.356A>G; p.His119Arg) of NEK3, encoding a NIMA (never in mitosis A)-related kinase, in two affected individuals, respectively. Protein levels of NEK3 were abrogated in Patient-1 with biallelic loss-of function (LoF) NEK3 mutations that causes premature stop codon. Subsequence transcriptome analysis revealed that NNMT (nicotinamide N-methyltransferase) and SIRT2 (sirtuin2) was upregulated by NEK3 knockdown in human retinal pigment epithelial (RPE) cells in vitro, which associates α-tubulin deacetylation by western blot and immunofluorescence. Transmission electron microscopy (TEM) analysis further identified defective ciliary ultrastructure in Patient-1. Furthermore, inner ring components of nuclear pore complex (NPC) including nucleoporin (NUP)205, NUP188, and NUP155 were significantly downregulated in NEK3-silenced cells. In conclusion, we identified biallelic mutations of NEK3 predispose individual to abnormal cardiac left–right patterning via SIRT2-mediated α-tubulin deacetylation and downregulation of inner ring nucleoporins. Our study suggested that NEK3 could be a candidate gene for human ciliopathies.

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Section: Resultsmentioning

confidence: 99%

Biallelic loss of function NEK3 mutations deacetylate α-tubulin and downregulate NUP205 that predispose individuals to cilia-related abnormal cardiac left–right patterning

Zhang¹,

Chen²,

Zeng³

et al. 2020

Cell Death Dis

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“…Based on these sensitive site detections, the regions of the NPC proteins in the mutant cells appeared to be different from those in the wildtype cells. It is important to note that NUP153-LMNA interactions have already been suggested to be linked to laminopathies, including DCM, [56,57] although the detailed mechanism remains unknown. By integration with the proteomic results in this work, the sites on NUP153 that are tagged with more and less AdP upon mutation can be considered important regions where the interactions of NUP153 with LMNA are largely influenced by the mutation in relation to DCM.…”

Section: Proteomic Comparison Study Of Lmna and Its Mutant For The Di...mentioning

confidence: 99%

A Combination of Bio‐Orthogonal Supramolecular Clicking and Proximity Chemical Tagging as a Supramolecular Tool for Discovery of Putative Proteins Associated with Laminopathic Disease

Sim

Lee

Kim

et al. 2023

Small

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surrounding a mutant protein is important for elucidating the pathological processes of diseases caused by mutations. Lamin A (LMNA) is a critical nucleoskeletal protein that forms the nuclear lamina underlying the inner nuclear membrane through PPIs among neighboring associated proteins. LMNA is involved in orchestrating various biological processes, including epigenetic regulation, chromatin organization, and signal transduction. [2] More than 400 LMNA mutants identified from patients cause malfunctions of biological processes resulting in laminopathies, including Emery-Dreifuss muscular dystrophy (EDMD), familial partial Dunnigan lipodystrophy type 2 (FPDL2), and Hutchinson-Gilford progeria syndrome (HGPS). [3] In particular, L85R mutants of LMNA (LMNA-L85R) are involved in causing dilated cardiomyopathy (DCM), a heart muscle disease. [4] The identification of the proteins adjacent to the mutants in live cells is crucial to understanding the pathological mechanisms of the mutation. Although proteomic studies using yeast two-hybrid assay, protein microarray, and affinity purification coupled with mass spectrometry have been reported, [5][6][7][8] accurate proteomic analysis is hindered by the drawbacks of these approaches, including the use of non-human cells, irregular Protein mutations alter protein-protein interactions that can lead to a number of illnesses. Mutations in laminA (LMNA) have been reported to cause laminopathies. However, the proteins associated with the LMNA mutation have mostly remained unexplored. Herein, a new chemical tool for proximal proteomics is reported, developed by a combination of proximity chemical tagging and a bio-orthogonal supramolecular latching based on cucurbit[7]uril (CB[7])based host-guest interactions. As this host-guest interaction acts as a noncovalent clickable motif that can be unclicked on-demand, this new chemical tool is exploited for reliable detection of the proximal proteins of LMNA and its mutant that causes laminopathic dilated cardiomyopathy (DCM). Most importantly, a comparison study reveals, for the first time, mutant-dependent alteration in LMNA proteomic environments, which allows to identify putative laminopathic DCM-linked proteins including FOXJ3 and CELF2. This study demonstrates the feasibility of this chemical tool for reliable proximal proteomics, and its immense potential as a new research platform for discovering biomarkers associated with protein mutation-linked diseases.

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“…Nucleoporins (NUPs) are the critical molecular components for the assembly and function of the nuclear pore complex (NPC). The NPC is composed of 30 different nucleoporins that are each present in multiple copies [116] and contain cytoplasmic and nucleoplasmic filaments [117]. The filaments consist of microfilaments, intermediate filaments, and myosin filaments, which are all part of the cytoskeletal network.…”

Section: Variants In Nucleoporinsmentioning

confidence: 99%

Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

Wijk

Wijdeveld

et al. 2022

Cells

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The most common clinical tachyarrhythmia, atrial fibrillation (AF), is present in 1–2% of the population. Although common risk factors, including hypertension, diabetes, and obesity, frequently underlie AF onset, it has been recognized that in 15% of the AF population, AF is familial. In these families, genome and exome sequencing techniques identified variants in the non-coding genome (i.e., variant regulatory elements), genes encoding ion channels, as well as genes encoding cytoskeletal (-associated) proteins. Cytoskeletal protein variants include variants in desmin, lamin A/C, titin, myosin heavy and light chain, junctophilin, nucleoporin, nesprin, and filamin C. These cytoskeletal protein variants have a strong association with the development of cardiomyopathy. Interestingly, AF onset is often represented as the initial manifestation of cardiac disease, sometimes even preceding cardiomyopathy by several years. Although emerging research findings reveal cytoskeletal protein variants to disrupt the cardiomyocyte structure and trigger DNA damage, exploration of the pathophysiological mechanisms of genetic AF is still in its infancy. In this review, we provide an overview of cytoskeletal (-associated) gene variants that relate to genetic AF and highlight potential pathophysiological pathways that drive this arrhythmia.

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Nucleoporins in cardiovascular disease

Cited by 15 publications

References 150 publications

Biallelic loss of function NEK3 mutations deacetylate α-tubulin and downregulate NUP205 that predispose individuals to cilia-related abnormal cardiac left–right patterning

Biallelic loss of function NEK3 mutations deacetylate α-tubulin and downregulate NUP205 that predispose individuals to cilia-related abnormal cardiac left–right patterning

A Combination of Bio‐Orthogonal Supramolecular Clicking and Proximity Chemical Tagging as a Supramolecular Tool for Discovery of Putative Proteins Associated with Laminopathic Disease

Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

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