Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium.
Aged
Animals
Cell Communication
/ genetics
Cell Line
Cell Movement
/ genetics
Cell Nucleus
/ genetics
Cells, Cultured
Computational Biology
/ methods
Databases, Genetic
Endothelial Cells
/ metabolism
Endothelium
/ metabolism
Female
Gene Expression
Gene Expression Profiling
Gene Knockdown Techniques
Gene Ontology
Humans
Immunohistochemistry
Male
Membrane Proteins
/ genetics
Mice
Mice, Knockout
Middle Aged
Protein Transport
Stress, Mechanical
aortic valve stenosis
endothelial cells
nucleocytoplasmic transport
palmdelphin
Journal
Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763
Informations de publication
Date de publication:
16 11 2021
16 11 2021
Historique:
pubmed:
13
10
2021
medline:
4
1
2022
entrez:
12
10
2021
Statut:
ppublish
Résumé
PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the single nucleotide polymorphism rs7543130 informed about gene regulatory changes. ECs express the cytosolic We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced
Sections du résumé
BACKGROUND
PALMD (palmdelphin) belongs to the family of paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms in the
METHODS
Immunodetection and public database screening showed dominant expression of PALMD in endothelial cells (ECs) in brain and cardiovascular tissues including aortic valves. Mass spectrometry, coimmunoprecipitation, and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in small interferring RNA-treated EC cultures, knockout mice, and human valve samples. RNA sequencing of ECs and transcript arrays on valve samples from an aortic valve study cohort including patients with the single nucleotide polymorphism rs7543130 informed about gene regulatory changes.
RESULTS
ECs express the cytosolic
CONCLUSIONS
We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex alters the subcellular localization of RANGAP1 and XPO1, and leads to nuclear arrest of the XPO1 cargoes p53 and p21, accompanied by gene regulatory changes and loss of actin-dependent nuclear resilience. Combined, these consequences of reduced
Identifiants
pubmed: 34636652
doi: 10.1161/CIRCULATIONAHA.121.054182
pmc: PMC8589083
doi:
Substances chimiques
Membrane Proteins
0
PALMD protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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