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TMEM63B Regulates Nucleocytoplasmic Transport and Placental Development

ABSTRACT: The placenta is critical for embryonic development, orchestrating nutrient exchange, hormone production, and immune protection. Trophoblast proliferation and differentiation, governed by precise cell cycle regulation, are fundamental to placental development. Here, we identify TMEM63B, an osmo/mechano-sensitive ion channel, as a key regulator of trophoblast cell cycle progression and placental development. Our findings show that TMEM63B modulates nucleocytoplasmic transport (NCT), particularly through its impact on the Ran-XPO1-RanGAP1 complex, which governs the nuclear shuttling of key cell cycle regulators in response to mechanical cues. Loss of TMEM63B results in a reduction of Ran protein levels, destabilizing the export machinery and impairing the nuclear export of CDKN1A (p21), a critical cell cycle inhibitor. This disruption leads to defective trophoblast proliferation, placental dysfunction, and ultimately embryonic lethality. Our findings establish TMEM63B as a pivotal mechanosensitive molecule that regulates nucleocytoplasmic shuttling, providing new insights into how mechanical cues are integrated into nuclear mechanoresponses and placental development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290233 | GEO | 2026/05/11

REPOSITORIES: GEO

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Project 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.

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TMEM63B Regulates Nucleocytoplasmic Transport and Placental Development

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