The functions and mechanisms of post-translational modification in protein regulators of RNA methylation: Current status and future perspectives

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 253, P. 126773 - 126773

Published: Sept. 9, 2023

Language: Английский

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Interferons and interferon-related pathways in heart disease

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: April 11, 2024

Interferons (IFNs) and IFN-related pathways play key roles in the defence against microbial infection. However, these processes may also be activated during pathogenesis of non-infectious diseases, where they contribute to organ injury, or function a compensatory manner. In this review, we explore IFNs heart disease. We consider cardiac effects type I IFN-stimulated genes (ISGs); emerging role cyclic GMP-AMP synthase (cGAS)-stimulator interferon (STING) pathway; seemingly paradoxical II IFN, IFN-γ; varied actions regulatory factor (IRF) family transcription factors. Recombinant small molecule inhibitors mediators IFN receptor signaling are already employed clinic for treatment some autoimmune infections, cancers. There has been renewed interest because their involvement SARS-CoV-2 infection, relatively recent emergence cGAS-STING as pattern recognition receptor-activated pathway. Whether advances will ultimately result improvements care those experiencing disease remains determined.

Language: Английский

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Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates

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

Published: Feb. 13, 2025

The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents systematic design quinoline-containing papain-like protease (PLpro) inhibitors as potential antiviral drug candidates. By leveraging recently discovered Val70Ub binding site in PLpro, we designed a series quinoline analogs demonstrating potent PLpro inhibition and activity. Notably, X-ray crystal structures 6 lead compounds reveal that 2-aryl substitution can occupy either expected or BL2 groove flipped orientation. vivo Jun13296 exhibits favorable pharmacokinetic properties against nirmatrelvir-resistant mutants. In mouse model infection, treatment with significantly improves survival, reduces body weight loss lung viral titers, prevents tissue damage. These results underscore promising candidates, instilling hope for future treatment. inhibitor, Jun13296, displays efficacy infection inhibits mutants, rendering it candidate.

Language: Английский

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ISGylation of the SARS-CoV-2 N protein by HERC5 impedes N oligomerization and thereby viral RNA synthesis

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(9)

Published: Aug. 28, 2024

Interferon (IFN)-stimulated gene 15 (ISG15), a ubiquitin-like protein, is covalently conjugated to host immune proteins such as MDA5 and IRF3 in process called ISGylation, thereby promoting type I IFN induction limit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, whether SARS-CoV-2 can be directly targeted for ISGylation remains elusive. In this study, we identified nucleocapsid (N) protein major substrate catalyzed by E3 ligase HERC5; however, N readily removed through deISGylation papain-like protease (PLpro) activity NSP3. Mass spectrometry analysis that undergoes at four lysine residues (K266, K355, K387, K388), mutational these sites context replicon (N-4KR) abolished alleviated ISGylation-mediated inhibition viral RNA synthesis. Furthermore, our results indicated HERC5 targets preferentially phosphorylated regulate its oligomeric assembly. These findings reveal novel mechanism which machinery restrict illuminate how an intricate interplay (HERC5) enzymes coordinates regulates virus replication.IMPORTANCEThe role regulating cellular processes has been studied extensively; ISG15 conjugation influences proteins, particularly coronaviral largely unknown. Our study uncovered ISGylated modification impedes functional assembly into oligomers ultimately inhibiting This antiviral restriction antagonized PLpro deepens understanding regulation posttranslational modifications may open new avenues designing strategies COVID-19.

Language: Английский

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Multiorgan proteomic analysis of infected animal models predict potential host factors for chikungunya virus

MedComm, Journal Year: 2025, Volume and Issue: 6(1)

Published: Jan. 1, 2025

Abstract Chikungunya virus (CHIKV) is a mosquito‐borne alphavirus that primarily known for causing severe joint and muscle symptoms, but its pathological effects have extended beyond these tissues. In this study, we conducted comprehensive proteomic analysis across various organs in rodent nonhuman primate models to investigate CHIKV's impact on joints muscles identify key host factors involved pathogenesis. Our findings reveal significant species‐specific similarities differences immune responses metabolic regulation, with proteins like Interferon‐Stimulated Gene 15 (ISG15) Retinoic Acid‐Inducible I (RIG‐I) playing crucial roles the anti‐CHIKV defense. We observed upregulated downregulated status CHIKV‐infected rhesus monkeys mice, respectively. Additionally, identified such as S100 Calcium‐Binding Protein A8/A9 (S100A8/A9), Voltage‐Dependent Anion Channel 1/2 (VDAC1/2), Complement Component 3 (C3), Apoptosis‐Inducing Factor Mitochondria‐Associated 1 (AIFM1), Endothelial Cell‐Specific Chemotaxis Regulator (ECSCR), Kininogen (KNG1) may contribute CHIKV‐induced inflammation hemorrhage. These insights put emphases importance of understanding muscles, providing potential therapeutic targets enhancing our CHIKV This research underscores need appropriate animal studies informs development targeted therapies address systemic effects.

Language: Английский

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MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(14)

Published: April 4, 2025

The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like is crucial for regulating antiviral host responses. cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5K23R/K43R) two major sites, K23 K43, MDA5, were mutated. Primary cells derived from MDA5K23R/K43R exhibited abrogated endogenous impaired ability to form oligomeric assemblies, leading blunted cytokine responses RNA-agonist stimulation infection with encephalomyocarditis virus (EMCV) West Nile virus. Phenocopying MDA5-/- mice, EMCV displayed increased myocardial injury mortality, elevated viral titers, ablated induction cytokines chemokines compared WT mice. Molecular studies identified human HERC5 (and functional murine homolog HERC6) as primary E3 ligases responsible activation. Taken together, these findings establish importance CARD MDA5-mediated RNA restriction, promoting potential avenues immunomodulatory drug design anti-inflammatory applications.

Language: Английский

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Peripheral transcriptional responses to experimental SARS-CoV-2 inoculation in North American Elk cows and calves

Published: May 15, 2025

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a health risk for humans and other domestic wildlife species. Recently, North American elk has been identified as seropositive SARS-CoV-2, thus posing potential threat to mammals. In this work, we characterized the peripheral transcriptomic response experimental SARS-CoV-2 infection in calves adult elk. Results Significantly differentially expressed genes were at 2, 5, 14 days post inoculation (dpi) both age groups. Adult presented greatest number of (DE) all time points, including many associated with viral response, immune activation, antibody production, those disease (COVID-19), GO terms KEGG pathways. Calves DE responses 5 dpi well neurodegenerative-associated dpi. Both adults showed predicted activation ISGF3 IFN type I pathways and, globally, increased activity related pathway Conclusions Collectively, work provides valuable data characterizing diseases infection.

Language: Английский

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Discovery of Potential Drug Targeting Key Genes in Alzheimer’s Disease: Insights from Transcriptome Analysis and Molecular Docking

Journal of Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 74(2)

Published: May 27, 2024

Language: Английский

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Unconventional posttranslational modification in innate immunity

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: July 6, 2024

Pattern recognition receptors (PRRs) play a crucial role in innate immunity, and complex network tightly controls their signaling cascades to maintain immune homeostasis. Within the modification network, posttranslational modifications (PTMs) are at core of cascades. Conventional PTMs, which include phosphorylation ubiquitination, have been extensively studied. The regulatory unconventional involving unanchored ISGylation, SUMOylation, NEDDylation, methylation, acetylation, palmitoylation, glycosylation, myristylation, modulation pathways has increasingly investigated. This comprehensive review delves into emerging field PTMs highlights pivotal immunity.

Language: Английский

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Longitudinal Assessment of Nasopharyngeal Biomarkers Post-COVID-19: Unveiling Persistent Markers and Severity Correlations

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: 23(11), P. 5064 - 5084

Published: Oct. 11, 2024

SARS-CoV-19 infection provokes a variety of symptoms; most patients present mild/moderate symptoms, whereas small proportion progress to severe illness with multiorgan failure accompanied by metabolic disturbances requiring ICU-level care. Given the importance disease, researchers focused on identifying severity-associated biomarkers in infected as well markers associated suffering long-COVID. However, little is known about presence that remain few years after SARS-CoV-2 once fully recover symptoms. In this study, we evaluated persistent nasopharyngeal tract two SARS-Cov-2 asymptomatic patients, taking into account severity their (mild/moderate and infections). addition direct identification several components Coronavirus Infection Pathway those individuals suffered infections, describe herein 371 proteins canonical pathways define different adverse effects infections. The persistence these for up infection, along ability distinguish endured, highlights surprising exudate changes recovered patients.

Language: Английский

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