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Regulation of chromatin dynamics by a calcium-dependent nucleoskeleton

ABSTRACT: This project investigates the mechanisms by which growth factors selectively activate nuclear calcium signaling to regulate gene transcription. While it is established that growth factors trigger an increase in nuclear inositol 1,4,5-trisphosphate (IP3) and subsequent calcium release via intranuclear IP3 receptors (ITPRs), the downstream structural and functional consequences within the nucleoplasm remain under characterization. Our study reveals that this calcium signaling event leads to the transient assembly of an actin nucleoskeleton, which specifically associates with the intranuclear non-muscle myosin 2A (MYH9).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Dawidson Gomes

LAB HEAD: Dawidson Gomes

PROVIDER: PXD075767 | Pride | 2026-05-13

REPOSITORIES: Pride

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			Action	DRS
	QEp19-5879_Rodrigues_U2OS_WT_Control_1.mzid	Mzid
	QEp19-5879_Rodrigues_U2OS_WT_Control_1.mzid_QEp19-5879_Rodrigues_U2OS_WT_Control_1.MGF	Mzid
	QEp19-5879_Rodrigues_U2OS_WT_Control_1.raw	Raw
	QEp19-5883_Rodrigues_U2OS_WT_Control_2.mzid	Mzid
	QEp19-5883_Rodrigues_U2OS_WT_Control_2.mzid_QEp19-5883_Rodrigues_U2OS_WT_Control_2.MGF	Mzid

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Regulation of chromatin dynamics by a calcium-dependent nucleoskeleton

Project description:This project investigates the mechanisms by which growth factors selectively activate nuclear calcium signaling to regulate gene transcription. While it is established that growth factors trigger an increase in nuclear inositol 1,4,5-trisphosphate (IP3) and subsequent calcium release via intranuclear IP3 receptors (ITPRs), the downstream structural and functional consequences within the nucleoplasm remain under characterization. Our study reveals that this calcium signaling event leads to the transient assembly of an actin nucleoskeleton, which specifically associates with the intranuclear non-muscle myosin 2A (MYH9).

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Lamp1 proximity labeling proteomics in 5XFAD mice

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2025-02-20 | PXD048097 | Pride

Regulation of chromatin dynamics by a calcium-dependent nucleoskeleton

Project description:Growth factors selectively activate calcium signaling pathways in the cell nucleus, which in turn regulate gene transcription and other intra-nuclear events, but the specific way this is accomplished is not entirely understood. The present study shows that growth factors increase inositol 1,4,5-trisphosphate (IP3) in the nucleus, which in turn releases calcium from intranuclear IP3 receptors (ITPRs), which then leads to transient assembly of an actin nucleoskeleton that associates with intranuclear MYH9. Mass spectrometry suggests that much of the MYH9 cargo consists of components of the gene transcription machinery, while chromatin immunoprecipitation identified a number of specific genes that associate with the myosin in response to stimulation with growth factors. Together, these findings suggest that growth factors initiate gene transcription by transiently assembling an actin nucleoskeleton that works with MYH9 to bring specific genes to the transcription machinery.

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Subcellular proteomics and iPSC modeling uncover mechanisms of axonal pathology in Alzheimer’s disease

Project description:Amyloid deposits in Alzheimer’s disease (AD) are surrounded by large numbers of plaque-associated axonal spheroids (PAAS). PAAS disrupt axonal electrical conduction and neuronal network function and correlate with AD severity. However, the mechanisms of their formation remain largely unknown. To address this, we developed a proximity labeling approach to uncover the PAAS proteomes in human AD postmortem brains and mice. Proteomics analysis highlighted the activation of protein turnover, cytoskeleton dynamics and lipid transport. The PI3K/AKT/mTOR signaling, a master regulator of these biological processes, is also activated and expressed in PAAS, and strongly correlated with disease severity in AD humans. Using human iPSC modeling and Cre/lox mice, we found that mTOR inhibition markedly reduced PAAS formation in humans and mice. Together, we assembled a multidisciplinary toolkit and uncovered novel mechanisms of axonal spheroid pathology. This pipeline can be applied to examine new targets for axonal pathology in AD and neurodegeneration.

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Antisense oligonucleotide-mediated inclusion of the TRA2β ultraconserved poison exon induces the expression of a lncRNA with anti-tumor effects

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2024-12-20 | PXD042941 | Pride

Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis

Project description:Organelle transporters define metabolic compartmentalization and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR KO in cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening new avenues to explore regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.

2025-03-19 | PXD047327 | Pride

Protease-activated receptor 2 links protease activity with calcium waves during egg activation and blastomere cleavage

Project description:Successful initiation of animal development requires activation of the egg immediately prior to fusion of gamete pronucleii. In all taxa, this is initiated by waves of calcium transients which transverse across the egg. Calcium waves also occur at cleavage furrows during later blastula cytokinesis. Calcium is released from the endoplasmic reticulum through activation of 1,4,5-trisphosphate (IP3) receptors. Only a subset of the mechanisms employed to generate IP3 during vertebrate egg activation are defined, with strong evidence that other critical mechanisms exist. Serine proteases have been long implicated in egg activation and fertilisation. Here we report that treatment of zebrafish eggs with serine protease inhibitors leads to defective calcium wave propagation and failed egg activation. We further show that mutation of zebrafish Protease-activated receptor 2a (Par2a) also results in severe disruption of egg activation, leading to failed chorion elevation and ooplasmic segregation. Milder par2a mutants progress further, but then show abnormal blastomere cleavage. We observed that par2a mutants show decreased amplitude and duration of calcium transients. Restoring Ca++ or direct injection of IP3 ligand rescues egg activation aborted by either serine protease inhibitor treatment or by mutation of Par2a. We thus show that serine protease activity is a critical regulator of IP3 and subsequent calcium wave amplification during zebrafish egg activation, and link this to intracellular calcium release via the protease receptor, Par2a. This constitutes a novel signalling pathway critical for successful fertilisation.

2025-03-29 | GSE289416 | GEO

A single recurrent dominant variant in ITPR3 leads to a syndromic immunodeficiency

Project description:Intracellular calcium levels are finely tuned through intricate actions of a number of channels and transporters, including those at key endocellular stores, e.g. endoplasmic reticulum (ER), lysosomes, and mitochondria. Along with the highly homologous genes Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1) and 2 (ITPR2), ITPR3 encodes the IP3 receptor (IP3R), a key player in intracellular calcium release in animals. Here we report the first cases of ITPR3 defects in man leading to a primarily dysimmune phenotype. In four unrelated patients of diverse ethnicity, and suffering from a complex immunodeficiency syndrome, we report the same de novo pathogenic variant - c.7570C>T; p.Arg2524Cys - in ITPR3. Clinically, recurrent severe infectious episodes of viral and bacterial origins, features of ectodermal dysplasia and that of Charcot-Marie-Tooth disease were paramount. The identified variant does not affect gene transcription, yet it was structurally predicted and biologically proven to disrupt proper protein folding and function in vivo. This eventually leads to defective Calcium flux in patient cells, dysregulation of mitochondrial function and a broad dysimmune phenotype characterized primarily by a profound CD4 T cell lymphopenia associated with quasi absence of naïve CD4 and CD8 cells, itself mirrored by an increase in cognate memory cells. The Calcium signaling defect was recapitulated ex vivo through the introduction of this single variant in Jurkat cells. Moreover, site-directed mutagenesis displayed the exquisite sensitivity of Arg2524 to any amino acid change. In conclusion, a single unique recurrent de novo variant in ITPR3 leads to a novel syndromic immunodeficiency.

2023-07-05 | E-MTAB-13124 | biostudies-arrayexpress

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