PXD024887

PXD024887 is an original dataset announced via ProteomeXchange.

Title	Palmdelphin confers nuclear resilience to the aortic valve endothelium
Description	Background: Palmdelphin (PALMD), a protein of unknown function, belongs to the family of Paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms (SNPs) in the PALMD locus, which reduce its expression, are strong risk factors for development of calcific aortic valve stenosis (CAVS) and for severity of the disease. Methods: Public database screening and immunodetection of PALMD showed dominant expression in endothelial cells (ECs). Mass spectrometry allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in siRNA silenced EC cultures, in knockout mice and in human valve samples and EC cultures from patients. RNA sequencing on siRNA silenced cells and transcript arrays on valve samples from a Swedish SNP rs7543130 patient cohort informed about gene regulatory changes. Results: ECs express the cytoplasmic PALMD-KKVI splice variant, which was shown to exist in complex with RAN GTPase activating protein1 (RANGAP1). RANGAP1 regulates the activity of the GTPase RAN and thereby, nucleocytoplasmic shuttling via Exportin1 (XPO1). Reduced PALMD expression resulted in subcellular relocalization of RANGAP1 and XPO1, providing a mechanism for the gene regulatory changes established in PALMD-deficiency. Gene ontology analysis showed enrichment of actin and RHO GTPAse related terms in PALMD-silenced ECs. In accordance, PALMD-silenced ECs showed multiple changes in adhesive and migratory properties and cells were softer. In particular, PALMD-deficient ECs failed to form a perinuclear actin cap when exposed to flow. The perinuclear actin cap is known to provide protection against mechanical stress. Lack of the actin cap correlated with tilting of the nuclear long axis relative to the cell body, which was established in PALMD-deficient ECs, mice and patient valve samples. The loss of the actin cap may contribute to further dysregulated gene transcription eventually promoting calcific precipitations and inflammation in CAVS. Conclusions: We identify RANGAP1 as a PALMD partner in ECs. Disrupting the PALMD/RANGAP1 complex changes the subcellular localization of essential nucleocytoplasmic shuttling components, thereby instigating the loss of actin-dependent nuclear resilience, which in turn promotes further deterioration of gene expression patterns predisposing to the establishment of CAVS.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-16_23:48:15.268.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Georgios Mermelekas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-21 23:39:24	ID requested
⏵ 1	2022-02-16 23:48:16	announced

S, á, inz-Jaspeado M, Smith RO, Plunde O, Pawelzik SC, Jin Y, Nordling S, Ding Y, Aspenstr, ö, m P, Hedlund M, Bastianello G, Ascione F, Li Q, Demir CS, Fernando D, Daniel G, Franco-Cereceda A, Kroon J, Foiani M, Petrova TV, Kilimann MW, B, ä, ck M, Claesson-Welsh L, Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium. Circulation, 144(20):1629-1645(2021) [pubmed]

submitter keyword: Palmdelphin, endothelial, actin cap, RANGAP1, nucleocytoplasmic transport, calcific aortic valve stenosis

Lena Claesson-Welsh
contact affiliation	Uppsala University
contact email	lena.welsh@igp.uu.se
lab head
Georgios Mermelekas
contact affiliation	Karolinska Institutet
contact email	georgios.mermelekas@scilifelab.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024887
     1. Label: PRIDE project
     2. Name: Palmdelphin confers nuclear resilience to the aortic valve endothelium