Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr DOI Creative Commons

Shoya Fukatsu,

Maho Okawa,

Miyu Okabe

et al.

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(2), P. 1398 - 1412

Published: Feb. 5, 2024

Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between expression mutated CHMP2B displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that Asp148Tyr (D148Y) mutation, which preferentially displays phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed N1E-115 cell line, a model undergoes elongation. Second, these effects also accompanied by changes differentiation marker expression. Third, wild-type was indeed localized endosomal sorting complexes required transport (ESCRT)-like structures throughout cytoplasm. In contrast, D148Y mutation exhibited aggregation-like accumulated Golgi body. Fourth, among currently known stress regulators, levels Hsp47, has protective on body, decreased cells expressing mutation. Fifth, Arf4, another stress-signaling molecule, increased mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 small interfering (si)RNA, cellular phenotypes recovered. These suggest acting through signaling, negatively involved regulation morphological differentiation, providing evidence molecule controlling may be one potential therapeutic targets at molecular levels.

Language: Английский

Decoding ARF4 and EIF5B-Based Prognostic Signatures and Immune Landscape Following Insufficient Radiofrequency Ablation in Hepatocellular Carcinoma: Through Multi-Omics and Experimental Validation DOI Creative Commons

Yixin Zhang,

Yongpan Lu,

S. Zheng

et al.

Journal of Hepatocellular Carcinoma, Journal Year: 2025, Volume and Issue: Volume 12, P. 909 - 931

Published: May 1, 2025

Radiofrequency ablation (RFA) is pivotal in non-surgical hepatocellular carcinoma (HCC) treatments but poses a high postoperative recurrence risk, exceeding conventional surgeries. Insufficient tumor may trigger immune responses, promoting progression locally. Hence, this study seeks to pinpoint biomarkers improve treatment precision and prognostic accuracy for RFA patients. The utilized data from Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Consortium (ICGC) database investigate novel influencing the prognosis of patients undergoing insufficient radiofrequency (IRFA). Subsequently, an IRFA model was developed validated. Then, we employed Quantitative real time-Polymerase Chain Reaction (qPCR), Western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) techniques on human HCC cell lines animal validate ADP-ribosylation factor 4 (ARF4) Eukaryotic translation initiation 5B (EIF5B) expression relevance post-IRFA. In addition, knockdown ARF4 EIF5B performed evaluate proliferation, migration, invasion, epithelial-mesenchymal transition (EMT). Finally, transcriptome sequencing subsequently confirm extend our findings. were identified as critical targets affecting patient prognosis, forming basis risk model. High-risk scores correlated with poorer prognoses reduced responsiveness checkpoint inhibitors (ICIs) across multiple cancer types. Experimental validations confirmed protective role outcomes, while experiments suggested their involvement EMT models, potentially through pathways like P53 Transforming Growth Factor Beta(TGF-β) signaling pathway activation indicated by sequencing. have demonstrated promising potential following HCC. These findings suggest they could serve viable therapeutic aimed at mitigating post-RFA.

Language: Английский

Citations

0
Emerging Evidence of Golgi Stress Signaling for Neuropathies DOI Creative Commons

Remina Shirai,

Junji Yamauchi

Neurology International, Journal Year: 2024, Volume and Issue: 16(2), P. 334 - 348

Published: March 7, 2024

The Golgi apparatus is an intracellular organelle that modifies cargo, which transported extracellularly through the nucleus, endoplasmic reticulum, and plasma membrane in order. First, general function of reviewed and, then, stress signaling discussed. In addition to six main pathways, two pathways have been increasingly reported recent years are described this review. focus then shifts neurological disorders, examining major such as Alzheimer’s disease, Parkinson’s Huntington’s disease. review also encompasses findings related other diseases, including hypomyelinating leukodystrophy, frontotemporal spectrum disorder/amyotrophic lateral sclerosis, microcephaly, Wilson’s prion Most these disorders cause fragmentation stress. As a result, strong signals may act induce apoptosis.

Language: Английский

Citations

2
ARF4-mediated retrograde trafficking as a driver of chemoresistance in GBM DOI

Shreya Budhiraja,

Graysen McManus, Shivani Baisiwala

et al.

Neuro-Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: March 19, 2024

Abstract Background Cellular functions hinge on the meticulous orchestration of protein transport, both spatially and temporally. Central to this process is retrograde trafficking, responsible for targeting proteins nucleus. Despite its link many diseases, implications trafficking in glioblastoma (GBM) are still unclear. Methods To identify genetic drivers TMZ resistance, we conducted comprehensive CRISPR-knockout screening, revealing ADP-ribosylation factor 4 (ARF4), a regulator as major contributor. Results Suppressing ARF4 significantly enhanced sensitivity GBM patient-derived xenograft (PDX) models, leading improved survival rates (P < .01) primary recurrent lines. We also observed that exposure stimulates ARF4-mediated trafficking. Proteomics analysis cells with varying levels unveiled influence pathway EGFR signaling, increased nuclear overexpression treatment. Additionally, resolved RNA-sequencing patient tissues revealed substantial correlations between crucial (nEGFR) downstream targets, such MYC, STAT1, DNA-PK. Decreased activity DNA-PK, DNA repair nEGFR signaling contributes was suppressed levels. Notably, treatment DNA-PK inhibitor, KU-57788, mice PDX line resulted prolonged .01), highlighting promising therapeutic reliant Conclusions Our findings demonstrate development cementing viable strategy overcome chemoresistance GBM.

Language: Английский

Citations

1
Modulating Golgi Stress Signaling Ameliorates Cell Morphological Phenotypes Induced by CHMP2B with Frontotemporal Dementia-Associated p.Asp148Tyr DOI Creative Commons

Shoya Fukatsu,

Maho Okawa,

Miyu Okabe

et al.

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(2), P. 1398 - 1412

Published: Feb. 5, 2024

Some charged multivesicular body protein 2B (CHMP2B) mutations are associated with autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 7 (FTDALS7). The main aim of this study is to clarify the relationship between expression mutated CHMP2B displaying FTD symptoms and defective neuronal differentiation. First, we illustrate that Asp148Tyr (D148Y) mutation, which preferentially displays phenotypes, blunts neurite process elongation in rat primary cortical neurons. Similar results were observed N1E-115 cell line, a model undergoes elongation. Second, these effects also accompanied by changes differentiation marker expression. Third, wild-type was indeed localized endosomal sorting complexes required transport (ESCRT)-like structures throughout cytoplasm. In contrast, D148Y mutation exhibited aggregation-like accumulated Golgi body. Fourth, among currently known stress regulators, levels Hsp47, has protective on body, decreased cells expressing mutation. Fifth, Arf4, another stress-signaling molecule, increased mutant-expressing cells. Finally, when transfecting Hsp47 or knocking down Arf4 small interfering (si)RNA, cellular phenotypes recovered. These suggest acting through signaling, negatively involved regulation morphological differentiation, providing evidence molecule controlling may be one potential therapeutic targets at molecular levels.

Language: Английский

Citations

0