Structural basis of mRNA decay by the human exosome–ribosome supercomplex DOI Creative Commons
A.J. van der Kogel, Achim Keidel,

Matina-Jasemi Loukeri

et al.

Nature, Journal Year: 2024, Volume and Issue: 635(8037), P. 237 - 242

Published: Oct. 9, 2024

Abstract The interplay between translation and mRNA decay is widespread in human cells 1–3 . In quality-control pathways, exonucleolytic degradation of associated with translating ribosomes mediated largely by the cytoplasmic exosome 4–9 , which includes exoribonuclease complex EXO10 helicase SKI238 (refs. 10–16 ). can extract from ribosome expected to transfer it core through a bridging factor, HBS1L3 (also known as SKI7), but mechanisms this molecular handover remain unclear 7,17,18 Here we reveal how recruited (SKI7) an active ribosome-bound complex. We show that rather than sequential handover, direct physical coupling mechanism takes place, culminates formation exosome–ribosome supercomplex. Capturing structure during reveals continuous path RNA substrate threads 80S SKI2 into site SKI3 subunit directly binds also engages surface 40S subunit, establishing recognition platform collided disomes. Exosome thus work together single structural functional unit co-translational decay, coordinating their activities transient

Language: Английский

Relevance of mutation-derived neoantigens and non-classical antigens for anticancer therapies DOI Creative Commons

Belén Aparicio,

Patrick Theunissen, Sandra Hervás‐Stubbs

et al.

Human Vaccines & Immunotherapeutics, Journal Year: 2024, Volume and Issue: 20(1)

Published: Feb. 12, 2024

Efficacy of cancer immunotherapies relies on correct recognition tumor antigens by lymphocytes, eliciting thus functional responses capable eliminating cells. Therefore, important efforts have been carried out in antigen identification, with the aim understanding mechanisms response to immunotherapy and design safer more efficient strategies. In addition classical tumor-associated identified during last decades, implementation next-generation sequencing methodologies is enabling identification neoantigens (neoAgs) arising from mutations, leading development new neoAg-directed therapies. Moreover, there are numerous non-classical originated other sources methodologies. Here, we review relevance neoAgs different results obtained applying neoAg-based addition, types best approaches for their described. This will help increase spectrum targetable molecules useful immunotherapies.

Language: Английский

Citations

5
Calibrated ribosome profiling assesses the dynamics of ribosomal flux on transcripts DOI Creative Commons
Kotaro Tomuro, Mari Mito, Hirotaka Toh

et al.

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

Published: Aug. 26, 2024

Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool for elucidating the regulatory mechanism protein synthesis. However, current method substantial issues: contamination by rRNAs and lack appropriate methods to measure numbers in transcripts. Here, we overcome these hurdles through development "Ribo-FilterOut", separation footprints from subunits ultrafiltration, "Ribo-Calibration", relies external spike-ins stoichiometrically defined mRNA-ribosome complexes. A combination approaches estimates number ribosomes transcript, translation initiation rate, overall events before its decay, all genome-wide manner. Moreover, our reveals allocation under heat shock stress, during aging, across cell types. Our strategy modified profiling measures kinetic stoichiometric parameters cellular transcriptome. faces issues with rRNA measurements authors develop Ribo-FilterOut Ribo-Calibration, can be used estimate various conditions.

Language: Английский

Citations

5
Regulation of inflammatory diseases via the control of mRNA decay DOI Creative Commons
Masanori Yoshinaga, Osamu Takeuchi

Inflammation and Regeneration, Journal Year: 2024, Volume and Issue: 44(1)

Published: March 15, 2024

Abstract Inflammation orchestrates a finely balanced process crucial for microorganism elimination and tissue injury protection. A multitude of immune non-immune cells, alongside various proinflammatory cytokines chemokines, collectively regulate this response. Central to regulation is post-transcriptional control, governing gene expression at the mRNA level. RNA-binding proteins such as tristetraprolin, Roquin, Regnase family, along with RNA modifications, intricately dictate decay pivotal mediators regulators in inflammatory Dysregulated activity these factors has been implicated numerous human diseases, underscoring significance regulation. The increasing focus on targeting mechanisms presents promising therapeutic strategy autoimmune diseases. This review offers an extensive overview during responses, delving into recent advancements, their implications strides made exploitation.

Language: Английский

Citations

4
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
Selectively advantageous instability in biotic and pre-biotic systems and implications for evolution and aging DOI Creative Commons
John Tower

Frontiers in Aging, Journal Year: 2024, Volume and Issue: 5

Published: May 16, 2024

Rules of biology typically involve conservation resources. For example, common patterns such as hexagons and logarithmic spirals require minimal materials, scaling laws energy. Here a relationship with the opposite theme is discussed, which selectively advantageous instability (SAI) one or more components replicating system, cell. By increasing complexity SAI can have benefits in addition to generation energy mobilization building blocks. involves potential cost system for materials and/or required create unstable component, some cases, its active degradation. well-studied cells. Short-lived transcription signaling factors enable rapid response changing environment, turnover critical replacement damaged macromolecules. The gene set viable cell includes proteases nuclease, suggesting essential life. promotes genetic diversity several ways. Toxin/antitoxin systems promote maintenance genes, mitochondria facilitates uniparental transmission. creating two distinct states, subject different selective pressures, maintain diversity. synthetic replicators favors replicator cycling, promoting emergence increased complexity. Both classical recent computer modeling reveals SAI. may be involved at additional levels biological organization. In summary, reproductive fitness, aging through loss resources deleterious alleles.

Language: Английский

Citations

4
Cooperative and Independent Functionality of tmRNA and SmpB in Aeromonas veronii: A Multifunctional Exploration Beyond Ribosome Rescue DOI Open Access
Tian Bai, Juanjuan Li,

Xue Chi

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 409 - 409

Published: Jan. 6, 2025

The trans-translation system, mediated by transfer-messenger RNA (tmRNA, encoded the ssrA gene) and its partner protein SmpB, helps to release ribosomes stalled on defective mRNA targets incomplete products for hydrolysis. Knocking out smpB genes in various pathogens leads different phenotypic changes, indicating that they have both cooperative independent functionalities. This study aimed clarify functional relationships between tmRNA SmpB Aeromonas veronii, a pathogen poses threats aquaculture human health. We characterized expression dynamics of at growth stages pathogen, assessed responses deletion strains ΔssrA ΔsmpB environmental stressors carbon source supplementations, identified gene-regulatory networks involving integrating transcriptomic analyses. Our results showed gene maintained stable throughout bacterial period, while exhibited upregulated response nutrient deficiencies. Compared wild type, attenuated resistance most stress conditions. However, independently responded starvation, specifically reduced lower concentrations Fe3+ higher Na+ ions, as well increased utilization β-Methyl-D-glucoside. analysis supported these results, demonstrating cooperate under nutrient-deficient conditions but operate nutrient-rich environments. Phenotypic experiments confirmed SsrA collaboratively regulate involved siderophore synthesis iron uptake systems extracellular deficiency. findings present provide crucial insights into functions system highlight new roles beyond trans-translation.

Language: Английский

Citations

0
Exploring the protective role of caffeine against Taraxacum-Induced ribotoxic stress mediated through autophagy and mitochondrial depolarization DOI Creative Commons
Chien-Jung Lin, Shuting Liu, Zih-Syuan Wu

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 21, 2025

Language: Английский

Citations

0
The ribosome as a platform to coordinate mRNA decay DOI Creative Commons
Martin Müller, Thomas Becker, Timo Denk

et al.

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(4)

Published: Jan. 30, 2025

Messenger RNA (mRNA) homeostasis is a critical aspect of cellular function, involving the dynamic interplay between transcription and decay processes. Recent advances have revealed that ribosome plays central role in coordinating mRNA decay, challenging traditional view free primary substrate for degradation. This review examines mechanisms whereby ribosomes facilitate both licensing execution decay. involves factors such as Ccr4-Not complex, small MutS-related domain endonucleases, various quality control pathways. We discuss how translational fidelity, well presence nonoptimal codons collisions, can trigger pathways nonstop no-go Furthermore, we highlight direct association canonical exonucleases, Xrn1 Ski-exosome system, with ribosome, underscoring ribosome's multifaceted platform regulatory processes governing stability. By integrating recent findings, this offers comprehensive overview structural basis not only translation but also serve hubs coordination.

Language: Английский

Citations

0
The SETDB1-PC4-UPF1 post-transcriptional machinery controls periodic degradation of CENPF mRNA and maintains mitotic progression DOI
Qimei Pan, Peng Luo, Yuntan Qiu

et al.

Cell Death and Differentiation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Language: Английский

Citations

0
Coupling mechanisms coordinating mRNA translation with stages of the mRNA lifecycle DOI Creative Commons
Valeria Famà, Lucia Coscujuela Tarrero,

Roberto Albanese

et al.

RNA Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Gene expression involves a series of consequential processes, beginning with mRNA synthesis and culminating in translation. Traditionally studied as linear sequence events, recent findings challenge this perspective, revealing coupling mechanisms that coordinate key steps gene expression, even when spatially temporally distant. In review, we focus on translation, the final stage examine its stages metabolism: synthesis, processing, export, decay. For each these provide an overview known instances Furthermore, discuss role high-throughput technologies uncovering intricate interactions genome-wide scale. Finally, highlight challenges propose future directions to advance our understanding how orchestrate robust adaptable programs.

Language: Английский

Citations

0