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Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium

Sáinz-Jaspeado, Miguel and Smith, Ross O. and Plunde, Oscar and Pawelzik, Sven-Christian and Jin, Yi and Nordling, Sofia and Ding, Yindi and Aspenström, Pontus and Hedlund, Marie and Bastianello, Giulia and Ascione, Flora and Li, Qingsen and Demir, Cansaran Saygili and Fernando, Dinesh and Daniel, Geoffrey and Franco-Cereceda, Anders and Kroon, Jeffrey and Foiani, Marco and Petrova, Tatiana V. and Kilimann, Manfred W. and Bäck, Magnus and Claesson-Welsh, Lena (2021). Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium. Circulation. 144 , 1629-1645
[Research article]

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Abstract

Background: Palmdelphin (PALMD) belongs to the family of Paralemmin proteins implicated in cytoskeletal regulation. Single nucleotide polymorphisms (SNPs) in the PALMD locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis (CAVS) and predict severity of the disease.
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, co-immunoprecipitation and immunofluorescent staining allowed identification of PALMD partners. The consequence of loss of PALMD expression was assessed in siRNA-treated EC cultures, in 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 SNP rs7543130, informed about gene regulatory changes.
Results: ECs express the cytosolic PALMD-KKVI splice variant, which associated 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, and nuclear arrest of the XPO1 cargoes p53 and p21. This indicates an important role for PALMD in nucleocytoplasmic transport and consequently, in gene regulation due to the impact on localization of transcriptional regulators. Changes in EC responsiveness upon loss of PALMD expression included failure to form a perinuclear actin cap when exposed to flow, indicating lack of protection against mechanical stress. Loss of the actin cap correlated with misalignment of the nuclear long axis relative to the cell body, observed in PALMD-deficient ECs, Palmd−/− mouse aorta and human aortic valve samples derived from CAVS patients. In agreement with these changes in EC behavior, gene ontology analysis showed enrichment of nuclear- and cytoskeleton-related terms in PALMD-silenced ECs.
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 PALMD expression provide a mechanistic underpinning for PALMD's contribution to CAVS pathology.

Authors/Creators:Sáinz-Jaspeado, Miguel and Smith, Ross O. and Plunde, Oscar and Pawelzik, Sven-Christian and Jin, Yi and Nordling, Sofia and Ding, Yindi and Aspenström, Pontus and Hedlund, Marie and Bastianello, Giulia and Ascione, Flora and Li, Qingsen and Demir, Cansaran Saygili and Fernando, Dinesh and Daniel, Geoffrey and Franco-Cereceda, Anders and Kroon, Jeffrey and Foiani, Marco and Petrova, Tatiana V. and Kilimann, Manfred W. and Bäck, Magnus and Claesson-Welsh, Lena
Title:Palmdelphin Regulates Nuclear Resilience to Mechanical Stress in the Endothelium
Series Name/Journal:Circulation
Year of publishing :2021
Volume:144
Page range:1629-1645
Number of Pages:17
ISSN:0009-7322
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Immunology in the medical area
URN:NBN:urn:nbn:se:slu:epsilon-p-113991
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-113991
Additional ID:
Type of IDID
DOI10.1161/CIRCULATIONAHA.121.054182
ID Code:26278
Faculty:S - Faculty of Forest Sciences
Department:(S) > Department of Forest Biomaterials and Technology
Deposited By: SLUpub Connector
Deposited On:06 Dec 2021 11:25
Metadata Last Modified:10 Mar 2022 14:37

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