KIS counteracts PTBP2 and regulates alternative exon usage in neurons DOI Creative Commons
Marcos Moreno-Aguilera, A Neher,

Mònica B. Mendoza

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: April 10, 2024

Alternative RNA splicing is an essential and dynamic process in neuronal differentiation synapse maturation, dysregulation of this has been associated with neurodegenerative diseases. Recent studies have revealed the importance RNA-binding proteins regulation programs. However, molecular mechanisms involved control these regulators are still unclear. Here, we show that KIS, a kinase upregulated developmental brain, imposes genome-wide alteration exon usage during mice. KIS contains protein-recognition domain common to spliceosomal components phosphorylates PTBP2, counteracting role factor exclusion. At level, phosphorylation unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 hnRNPM, hinders capability complex. Furthermore, display strong opposing functional interactions synaptic spine emergence maturation. Taken together, our data uncover post-translational link transcriptional alternative programs development.

Language: Английский

The C-terminal end of PLIN1 displays structural disorder DOI
Edgar D. Páez-Pérez, Miriam Livier Llamas-García, Gabriela M. Montero-Morán

et al.

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 42, P. 101963 - 101963

Published: Feb. 28, 2025

Language: Английский

Citations

0
Phosphorylation modulates secondary structure of intrinsically disorder regions in RNA polymerase II DOI Creative Commons
Wei Chen, Tatiana N. Laremore, Neela H. Yennawar

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108533 - 108533

Published: April 1, 2025

Language: Английский

Citations

0
Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation DOI Creative Commons
Xiuchun Li,

Xiayan Zhu,

Yangyue Wang

et al.

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: 45(9), P. 1861 - 1878

Published: May 8, 2024

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies addressed the effect and pharmacological mechanism of CANA in treatment PH. Therefore, our study aimed investigate treating First, suppressed increased pulmonary artery pressure, right ventricular hypertrophy, vascular remodeling both mouse rat PH models. Network pharmacology, transcriptomics, biological results suggested that could ameliorate by suppressing excessive oxidative stress smooth muscle cell proliferation partially through activation PPARγ. Further demonstrated inhibited phosphorylation PPARγ at Ser225 (a serine site PPARγ), thereby promoting nuclear translocation increasing its ability resist proliferation. Taken together, not only highlighted potential on but also revealed CANA-induced inhibition increases capacity counteract inhibits These findings may stimulate further research encourage future clinical trials exploring therapeutic treatment.

Language: Английский

Citations

3
Lactylome analysis reveals potential target modified proteins in the retina of form-deprivation myopia DOI Creative Commons
Jiaojiao Feng, Xiaoniao Chen, Runkuan Li

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(9), P. 110606 - 110606

Published: July 29, 2024

The biological mechanisms underlying the development of myopia have not yet been completely elucidated. retina is critical for visual signal processing, which primarily utilizes aerobic glycolysis to produce lactate as a metabolic end product. Lactate facilitates lysine lactylation (Kla), posttranslational modification essential transcriptional regulation. This study found increased glycolytic flux and accumulation in retinas form-deprived myopic guinea pigs. Subsequently, comprehensive analysis Kla levels retinal proteins revealed that was upregulated at 124 sites 92 downregulated three proteins. Functional enrichment protein interaction analyses showed significant pathways related energy metabolism, including glutathione glycolysis, hypoxia-inducible factor-1 signaling pathway. Parallel-reaction monitoring confirmed data reliability. These findings suggest connection between metabolism imbalance, providing new insights into pathogenesis myopia.

Language: Английский

Citations

3
Effects of Microplastic Accumulation on Neuronal Death After Global Cerebral Ischemia DOI Creative Commons

Dong Yeon Kim,

Min Kyu Park, Hyun Wook Yang

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(4), P. 241 - 241

Published: Feb. 7, 2025

Brain ischemia, a condition in which the brain is deprived of blood flow, can lead to stroke due blocked or unstable vessels. Global cerebral ischemia (GCI), characterized by an interruption deprives oxygen and nutrients, producing reactive species (ROS) that trigger cell death, kills nerve cells. Microplastics (MPs), tiny environmental pollutants, enter human body through contaminated food, water, disposable items, cosmetics, more. Once brain, MPs increase neuroinflammation overstimulating inflammatory factors such as microglia. also damage neurons scratching myelin microtubules, slowing signal transduction, causing cognitive impairment, leading neuronal death. Furthermore, microtubule may result release phosphorylated tau proteins, potentially linked Alzheimer's disease. We hypothesized could exacerbate destruction after GCI, increased To test this hypothesis, we administered (0.5 µm) orally at dose 50 mg/kg before inducing GCI. Staining techniques Fluoro-Jade B (FJB), ionized calcium-binding adaptor molecule 1 (Iba-1), cluster differentiation 68 (CD68), basic protein (MBP), microtubule-associated 2 (MAP2) were used, along with Western blot analysis for interleukin-6 (IL-6), TNF-α, tau-5, phospho-tau (S396) evaluate effects on neuroinflammation, destruction. The results showed MP accumulation significantly disruption, death GCI-MP group compared GCI-vehicle group. Therefore, study suggests daily life contribute exacerbation disease, severe

Language: Английский

Citations

0
Rethinking transcription factor dynamics and transcription regulation in eukaryotes DOI
Reiner A. Veitia

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Role of charges in a dynamic disordered complex between an IDP and a folded domain DOI Creative Commons
Katrine Bugge, Andrea Sottini, Miloš T. Ivanović

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 4, 2025

Abstract Protein complexes involving intrinsically disordered proteins (IDPs) cover a continuum from IDPs that fully fold upon binding to remain in the complex. Here we demonstrate case of charge-driven interactions folded domain with an oppositely charged IDP remains completely Using negatively and prothymosin α positively globular histone H1.0, show they form low-micromolar-affinity complex without fixed relative orientations or persistent contacts between specific residues. 25 charge variants domain, find affinity can be modulated both by net clustering on indicating some selectivity highly complexes. Our results highlight protein provide surface onto which bind while retaining disorder. We expect more such exist.

Language: Английский

Citations

0
Structural basis of human Mediator recruitment by the phosphorylated transcription factor Elk-1 DOI Creative Commons
Didier Monté,

Zoé Lens,

Frédérique Dewitte

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 22, 2025

Abstract One function of Mediator complex subunit MED23 is to mediate transcriptional activation by the phosphorylated transcription factor Elk-1, in response Ras-MAPK signaling pathway. Using cryogenic electron microscopy, we solve a 3.0 Å structure human complexed with domain Elk-1. Elk-1 binds via hydrophobic sequence PSIHFWSTLS P containing one residue (S383 p ), which forms tight turn around central Phenylalanine. Binding induces allosteric changes that propagate opposite face subunit, resulting dynamic behavior 19-residue segment, alters molecular surface MED23. We design specific mutation (G382F) disrupts Elk­-1 binding and consequently impairs Elk-1-dependent serum-induced target genes Ras-Raf-MEK-ERK The provides details insights into subunit-transcription interface.

Language: Английский

Citations

0
Poly(ADP-ribose)-binding protein RCD1 is a plant PARylation reader regulated by Photoregulatory Protein Kinases DOI Creative Commons
Julia P. Vainonen, Richard Gossens, Julia Krasensky-Wrzaczek

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: April 19, 2023

Abstract Poly(ADP-ribosyl)ation (PARylation) is a reversible post-translational protein modification that has profound regulatory functions in metabolism, development and immunity, conserved throughout the eukaryotic lineage. Contrary to metazoa, many components mechanistic details of PARylation have remained unidentified plants. Here we present transcriptional co-regulator RADICAL-INDUCED CELL DEATH1 (RCD1) as plant PAR-reader. RCD1 multidomain with intrinsically disordered regions (IDRs) separating its domains. We reported earlier regulates stress-tolerance by interacting numerous transcription factors (TFs) through C-terminal RST domain. This study suggests N-terminal WWE PARP-like domains, well connecting IDR play an important role for function. show binds PAR vitro via domain PAR-binding determines localization nuclear bodies (NBs) vivo. Additionally, found function stability controlled Photoregulatory Protein Kinases (PPKs). PPKs localize NBs phosphorylate at multiple sites affecting stability. work proposes mechanism negative regulation plants, which localizes NBs, TFs degraded after phosphorylation PPKs.

Language: Английский

Citations

8
Virus-modified paraspeckle-like condensates are hubs for viral RNA processing and their formation drives genomic instability DOI Creative Commons
Katherine L. Harper,

Elena M. Harrington,

Connor Hayward

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 26, 2024

Abstract The nucleus is a highly organised yet dynamic environment containing distinct membraneless nuclear bodies. This spatial separation enables subset of components to be concentrated within biomolecular condensates, allowing efficient and discrete processes occur which regulate cellular function. One such body, paraspeckles, are comprised multiple paraspeckle proteins (PSPs) built around the architectural RNA, NEAT1_2 . Paraspeckle function fully elucidated but has been implicated in variety developmental disease scenarios. We demonstrate that Kaposi’s sarcoma-associated herpesvirus (KSHV) drives formation structurally paraspeckles with dramatically increased size altered protein composition required for productive lytic replication. highlight these virus-modified form adjacent virus replication centres, potentially functioning as RNA processing hubs viral transcripts during infection. Notably, we reveal PSP sequestration into result genome instability both KSHV Epstein Barr (EBV) infection, implicating their virus-mediated tumourigenesis.

Language: Английский

Citations

3