Modulation of NBAS-Related Functions in the Early Response to SARS-CoV-2 Infection DOI Open Access
Valentina Granata, Isabel Pagani, Emanuela Morenghi

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2634 - 2634

Published: Jan. 30, 2023

Upon infection, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is predicted to interact with diverse cellular functions, such as the nonsense-mediated decay (NMD) pathway, suggested by identification of core NMD factor upframeshift-1 (UPF1) in SARS-CoV-2 interactome, and retrograde transport from Golgi endoplasmic reticulum (ER) through reticulum-Golgi intermediate compartment (ERGIC), where coronavirus assembly occurs. Here, we investigated expression localization neuroblastoma-amplified sequence (NBAS) protein, a UPF1 partner for at ER, participating also transport, its functional partners, early time points after infection human lung epithelial cell line Calu3. We found significant decrease DExH-Box Helicase 34 (DHX34), suppressor morphogenetic effect on genitalia 5 (SMG5), SMG7 6 h post-infection, followed increase these genes UPF2 9 post-infection. Conversely, NBAS other coding factors were not modulated. Known substrates related stress (Growth Arrest Specific 5, GAS5; transducin beta-like 2, TBL2; DNA damage-inducible transcript 3, DDIT3) increased infected cells, possibly result alterations pathway direct infection. that unconventional SNARE ER 1, USE1 (p31) Zeste White 10 homolog, ZW10, partners function, significantly over cells. Co-localization proteins did change within 24 nor it differ versus non-infected cells 1 infection; similarly, co-localization p31 was altered this short frame. Finally, both co-localize S N proteins. Overall, data are preliminary evidence an interaction between NBAS-related functions deserving further investigation.

Language: Английский

Translation‐coupled mRNA quality control mechanisms DOI Creative Commons
Laura Monaghan, Dáša Longman, Javier F. Cáceres

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(19)

Published: Aug. 22, 2023

Abstract mRNA surveillance pathways are essential for accurate gene expression and to maintain translation homeostasis, ensuring the production of fully functional proteins. Future insights into quality control will enable us understand how cellular levels controlled, defective or unwanted mRNAs can be eliminated, dysregulation these contribute human disease. Here we review translation‐coupled mechanisms, including non‐stop no‐go decay pathways, describing their shared trans‐acting factors, differences. We also describe advances in our understanding nonsense‐mediated (NMD) pathway, highlighting recent mechanistic findings, discovery novel as well role NMD physiology its impact on

Language: Английский

Citations

45
Readthrough compounds for nonsense mutations: bridging the translational gap DOI Creative Commons
Sacha Spelier, Eveline P.M. van Doorn, Cornelis K. van der Ent

et al.

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(4), P. 297 - 314

Published: Feb. 22, 2023

Approximately 10% of all pathological mutations are nonsense that responsible for several severe genetic diseases which no treatment regimens currently available. The most widespread strategy treating is by enhancing ribosomal readthrough premature termination codons (PTCs) to restore the production full-length protein. In past decade compounds with potential have been identified. However, although preclinical results on these promising, clinical studies not yielded positive outcomes. We review and research related characterize factors contribute observed translational gap.

Language: Английский

Citations

33
Cytoplasmic mRNA decay and quality control machineries in eukaryotes DOI
Megan E. Dowdle, Jens Lykke‐Andersen

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Language: Английский

Citations

1
The eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center DOI
João P. L. Coelho, Matthew C. J. Yip, Keely Oltion

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(7), P. 877 - 884

Published: Jan. 3, 2024

Language: Английский

Citations

8
Coronavirus takeover of host cell translation and intracellular antiviral response: a molecular perspective DOI Creative Commons
Evangelos D. Karousis, Katharina Schubert, Nenad Ban

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(2), P. 151 - 167

Published: Jan. 10, 2024

Coronaviruses are a group of related RNA viruses that cause respiratory diseases in humans and animals. Understanding the mechanisms translation regulation during coronaviral infections is critical for developing antiviral therapies preventing viral spread. Translation single-stranded genome host cell cytoplasm an essential step life cycle coronaviruses, which affects cellular mRNA landscape many ways. Here we discuss various strategies control, including how members Betacoronavirus genus shut down suppress innate immune functions, as well role non-structural protein 1 (Nsp1) process. We also outline fate RNA, considering stress response triggered infected cells, describe unique features contribute to programmed ribosomal -1 frameshifting, editing, shutdown evasion.

Language: Английский

Citations

8
Nonsense-mediated mRNA decay in neuronal physiology and neurodegeneration DOI Creative Commons

Marija Petrić Howe,

Rickie Patani

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(10), P. 879 - 892

Published: Aug. 3, 2023

The processes of mRNA export from the nucleus and subsequent translation in cytoplasm are particular relevance eukaryotic cells. In highly polarised cells such as neurons, finely-tuned molecular regulation these serves to safeguard spatiotemporal fidelity gene expression. Nonsense-mediated decay (NMD) is a cytoplasmic translation-dependent quality control process that regulates expression wide range scenarios nervous system, including neurodevelopment, learning, memory formation. Moreover, NMD dysregulation has been implicated broad neurodevelopmental neurodegenerative disorders. We discuss how related aspects regulate key neuronal functions and, particular, we focus on evidence implicating pathogenesis neurodegeneration. Finally, therapeutic potential challenges targeting across spectrum largely untreatable neurological diseases.

Language: Английский

Citations

14
Alternative splicing coupled to nonsense-mediated decay coordinates downregulation of non-neuronal genes in developing mouse neurons DOI Creative Commons
Anna Zhuravskaya, Karen Yap, Fursham Hamid

et al.

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: June 20, 2024

Abstract Background The functional coupling between alternative pre-mRNA splicing (AS) and the mRNA quality control mechanism called nonsense-mediated decay (NMD) can modulate transcript abundance. Previous studies have identified several examples of such a regulation in developing neurons. However, systems-level effects AS-NMD this context are poorly understood. Results We developed an R package, factR2, which offers comprehensive suite analysis functions. Using tool, we conducted longitudinal gene expression pluripotent stem cells undergoing induced neuronal differentiation. Our uncovers hundreds events with significant potential to regulate expression. Notably, is significantly overrepresented specific groups developmentally downregulated genes. Particularly strong association downregulation detected for cassette exons stimulating NMD upon their inclusion into mature mRNA. By combining bioinformatic analyses CRISPR/Cas9 genome editing other experimental approaches show that NMD-stimulating regulated by RNA-binding protein PTBP1 dampen genes also provided evidence mRNAs temporally coordinated NMD-independent repression mechanisms. Conclusions study provides accessible workflow discovery prioritization targets. It further argues pathway plays widespread role neurons facilitating functionally related non-neuronal

Language: Английский

Citations

5
The sex-specific factor SOA controls dosage compensation in Anopheles mosquitoes DOI Creative Commons
Agata Kalita, Eric Marois, Magdalena Kozielska

et al.

Nature, Journal Year: 2023, Volume and Issue: 623(7985), P. 175 - 182

Published: Sept. 28, 2023

The Anopheles mosquito is one of thousands species in which sex differences play a central part their biology, as only females need blood meal to produce eggs. Sex differentiation regulated by chromosomes, but presence creates dosage imbalance between males (XY) and (XX). Dosage compensation (DC) can re-equilibrate the expression chromosomal genes. However, because DC mechanisms have been fully characterized few model organisms, key questions about its evolutionary diversity functional necessity remain unresolved1. Here we report discovery previously uncharacterized gene (sex chromosome activation (SOA)) master regulator malaria gambiae. Sex-specific alternative splicing prevents SOA protein females. male isoform encodes DNA-binding that binds promoters active X Expressing sufficient induce female cells. Male mosquitoes lacking or ectopically expressing exhibit misregulation, compatible with viability causes developmental delay. Thus, our molecular analyses non-model organism elucidates steps lead establishment chromosome-specific fine-tuning mechanism.

Language: Английский

Citations

11
UPF1 helicase orchestrates mutually exclusive interactions with the SMG6 endonuclease and UPF2 DOI Creative Commons
Lukas M Langer, Katharina Kurscheidt, J. Basquin

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(10), P. 6036 - 6048

Published: May 6, 2024

Abstract Nonsense-mediated mRNA decay (NMD) is a conserved co-translational surveillance and turnover pathway across eukaryotes. NMD has central role in degrading defective mRNAs also regulates the stability of significant portion transcriptome. The organized around UPF1, an RNA helicase that can interact with several NMD-specific factors. In human cells, degradation targeted begins cleavage event requires recruitment SMG6 endonuclease to UPF1. Previous studies have identified functional links between but underlying molecular mechanisms remained elusive. Here, we used mass spectrometry, structural biology biochemical approaches identify characterize short linear motif interacts cysteine/histidine-rich (CH) domain Unexpectedly, found UPF1–SMG6 interaction precluded when UPF1 CH engaged another factor, UPF2. Based on cryo-EM data, propose formation distinct SMG6-containing UPF2-containing complexes may be dictated by different conformational states connected RNA-binding status Our findings rationalize key metazoan advance our understanding regulating activity guiding substrate recognition endonuclease.

Language: Английский

Citations

4
Double-stranded RNA responses, neoantigen presentation and suppression of hepatocellular carcinoma through NMD inhibition via endonuclease SMG6 DOI Open Access
Enes S. Arpa, Virginie Ricci,

Ilja E. Shapiro

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

SUMMARY Nonsense-mediated mRNA decay (NMD) eliminates transcripts with premature termination codons, often resulting from mutations or RNA processing errors. While both pro-and anti-tumor NMD activities have been proposed, mechanistic and therapeutic insights into inhibition in cancer hindered by the lack of a suitable vivo model. We address this combining liver-specific, conditional Smg6 mutation – disabling endonuclease that cleaves NMD-regulated genetic hepatocellular carcinoma (HCC) SMG6 elevates NMD-sensitive abundance translation, promotes MHC presentation unique immunopeptides, enhances T-cell infiltration. Additionally, mutant specifically activates type-I interferon signaling via double-stranded (dsRNA) accumulation dsRNA-sensor MDA5, boosting innate immune responses. These pathways converge to halt HCC at an inflammatory stage. Our findings establish as key regulator dsRNA homeostasis activation, offering potential advancing our understanding regulation.

Language: Английский

Citations

0