Variants and vaccines impact nasal immunity over three waves of SARS-CoV-2

Nature Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

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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Regulation of viral replication by host restriction factors

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 23, 2025

Viral infectious diseases, caused by numerous viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), enterovirus (EV), human immunodeficiency (HIV), hepatitis B (HBV), and papillomavirus (HPV), pose a continuous threat to global health. As obligate parasites, rely on host cells replicate, have developed defense mechanisms counteract viral infection. Host restriction factors (HRFs) are critical components of the early antiviral response. These cellular proteins inhibit replication spread impeding essential steps in life cycle, such as entry, genome transcription replication, protein translation, particle assembly, release. This review summarizes current understanding how with primary focus their diverse against range viruses, SARS-CoV-2, virus, enteroviruses, papillomavirus. In addition, we highlight crucial role these shaping host-virus interactions discuss potential targets for drug development.

Language: Английский

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Ammonium chloride mitigates the amplification of fish virus by blocking autophagy-dependent replication

The Journal of Immunology, Journal Year: 2025, Volume and Issue: 214(2), P. 265 - 277

Published: Feb. 1, 2025

Ammonia fertilizer, primarily composed of ammonium chloride, is widely used in pond fish farming throughout Asia. Despite the belief that it possesses antiviral properties, underlying mechanisms remain unclear. Ammonium chloride (NH4Cl) has been demonstrated to act as a potent inhibitor autophagy, which by many viruses promote their proliferation during infection. It was therefore hypothesized effect ammonia fertilizers likely due inhibition autophagy viruses. The present study sought evaluate NH4Cl model several cells and zebrafish. findings administration after viral infection inhibited variety viruses, encompassing both DNA RNA Further studies have indicated obstructed autophagy-dependent virus spring viremia carp (SVCV) inhibiting autophagic flux. molecular mechanism revealed SVCV contributed polyubiquitination interferon regulatory factor 3 (IRF3) promoted degradation IRF3 through cargo receptor sequestosome 1 (SQSTM1/p62)-mediated selective autophagy. However, observed inhibit SVCV-mediated IRF3, thereby facilitating production interferon. Furthermore, N protein critical importance this process. Nevertheless, impeded process pathway. found highly efficacious controlling vivo vitro. can be concluded was, at least part,

Language: Английский

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E3 ubiquitin ligase MARCH5 positively regulates Japanese encephalitis virus infection by catalyzing the K27-linked polyubiquitination of viral E protein and inhibiting MAVS-mediated type I interferon production

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

ABSTRACT Membrane-associated RING-CH-type finger (MARCH) proteins, a class of E3 ubiquitin ligases, have been reported to be involved in the infection multiple viruses and regulation type I interferon (IFN) production. However, specific role mechanisms by which MARCH proteins influence Japanese encephalitis virus (JEV) remain poorly understood. Here, we systematically investigate functional relevance JEV replication examining effects siRNA-mediated knockdown MARCHs on viral infection. We identified MARCH5 as positive regulator replication. The knockout dramatically reduced yields, whereas its overexpression significantly enhanced Mechanistically, specifically interacts with envelope (E) protein promotes K27-linked polyubiquitination at lysine (K) residues 136 166. This ubiquitination enhances attachment permissive cells. Substituting these arginine (R) attenuated vitro virulence vivo . Furthermore, upregulated expression MARCH5. also discovered that degrades mitochondrial antiviral-signaling (MAVS) through ubiquitin-proteasome pathway catalyzing K48-linked ubiquitination, thereby inhibiting IFN production JEV-infected suppression further facilitates In conclusion, findings disclosed novel positively regulating revealed an important mechanism employed regulate innate immune response. IMPORTANCE is leading cause many countries Asia estimated 100,000 clinical human cases causes economic loss swine industry. Until now, there no clinically approved antiviral for treatment Although vaccination prophylaxis widely regarded most effective strategy preventing (JE), incidence JE continues rise. Thus, deeper understanding virus-host interaction will enrich our knowledge underlying identify targets development next-generation live-attenuated vaccines therapies. To best knowledge, this study first pro-viral host factor elucidated two distinct First, E mediates K136 K166 facilitate efficient attachment. double mutations K136R-K166R mice. Second, induced suppresses RIG-I-like receptor (RLR) signaling benefit downregulates conjugating polyubiquitin K286 MAVS, leads MAVS degradation pathway. summary, provides insights into played identifies sites could targeted attenuation therapeutics.

Language: Английский

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β-Coronaviruses exploit ESCRT for virion assembly and egress

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: May 23, 2025

ABSTRACT β-Coronaviruses assemble at the endoplasmic reticulum-to-Golgi compartment and exit cells through lysosomal trafficking pathway. However, molecular mechanisms of virion assembly egress are largely unknown. Here, we report that β-coronaviruses recruit endosomal sorting complexes required for transport (ESCRTs) to facilitate egress. The viral proteins N M interacted with ESCRT components TSG101 VPS28, respectively. Electron microscopy analysis revealed was disrupted by knockdown an early stage VPS28 a late stage. Knockdown MVB12A CHMP6 did not affect but inhibited Downregulation these factors or VPS4A, treatment antagonist tenatoprazole significantly production virion-like particles replication human coronavirus OC43. These findings indicate exploit suggest interaction interface between viruses could be target development broad-spectrum anti-coronavirus therapeutics. IMPORTANCE have caused disastrous pandemics may cause serious in future. Virion critical steps life cycle coronaviruses. despite extensive studies past few years, still Here show Treatment multiple β-coronaviruses. participates β-coronavirus might potential

Language: Английский

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Integrated Transcriptomic Analysis Reveals Reciprocal Interactions between SARS-CoV-2 Infection and Multi-Organ Dysfunction, Especially the Correlation of Renal Failure and COVID-19

Life, Journal Year: 2024, Volume and Issue: 14(8), P. 960 - 960

Published: July 30, 2024

The COVID-19 pandemic, which is caused by the SARS-CoV-2 virus, has resulted in extensive health challenges globally. While primarily targets respiratory system, clinical studies have revealed that it could also affect multiple organs, including heart, kidneys, liver, and brain, leading to severe complications. To unravel intricate molecular interactions between virus host tissues, we performed an integrated transcriptomic analysis investigate effects of on various with a particular focus relationship renal failure COVID-19. A comparative showed triggers systemic immune response kidney characterized significant upregulation cytokine chemokine secretion, along enhanced migration lymphocytes leukocytes. weighted gene co-expression network demonstrated induce tissue-specific transcriptional profiling. More importantly, single-cell sequencing patients exhibited lower metabolic activity lung epithelial B cells, reduced ligand-receptor interactions, especially CD226 ICAM, suggesting compromised response. trajectory less mature alveolar type 1 cells. Furthermore, these potential fibrosis hearts, increased extracellular matrix remodeling activities. However, there was no dysregulation liver failure. Candidate drugs prediction Drug Signatures database LINCS L1000 Antibody Perturbations Database underscored importance considering multi-organ management highlight therapeutic strategies, targeting viral entry replication, controlling tissue fibrosis, alleviating inflammation.

Language: Английский

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BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer

Pharmacological Research, Journal Year: 2024, Volume and Issue: 208, P. 107377 - 107377

Published: Aug. 28, 2024

The bromodomain and extraterminal domain (BET) family proteins serve as primary readers of acetylated lysine residues play crucial roles in cell proliferation differentiation. Dysregulation BET has been implicated tumorigenesis, making them important therapeutic targets. BET-bromodomain (BD) inhibitors BET-targeting degraders have developed to inhibit proteins. In this study, we found that the inhibitor MS645 exhibited superior antiproliferative activity than including ARV771, AT1, MZ1 dBET1 triple-negative breast cancer (TNBC) cells. Treatment with led dissociation BETs, MED1 RNA polymerase II from E2F1-3 promoter, resulting suppression transcription subsequent inhibition growth TNBC. contrast, while ARV771 displaced chromatin, it did not significantly alter expression. Mechanistically, induced BRD4 depletion at protein level, which markedly increased EGR1 This elevation subsequently recruited septin 2 9 promoters, enhancing promoting rate vitro vivo. Our findings provide valuable insights into differential mechanisms highlight potential developing molecules strategies for

Language: Английский

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Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 14, 2024

Abstract Identification of accurate biomarkers is still particularly urgent for improving the poor survival chronic obstructive pulmonary disease (COPD) patients. In this investigation, we aimed to identity potential in COPD via bioinformatics and next generation sequencing (NGS) data analysis. differentially expressed genes (DEGs) were identified using NGS dataset (GSE239897) from Gene Expression Omnibus (GEO) database. Subsequently, gene ontology (GO) pathway enrichment analysis was conducted evaluate underlying molecular mechanisms involved progression COPD. Protein-protein interaction (PPI), modules, miRNA-hub regulatory network TF-hub performed determine hub genes, miRNAs TFs. The receiver operating characteristic (ROC) diagnostic value genes. A total 956 overlapping DEGs (478 up regulated 478 down genes) dataset. mainly associated with GO functional terms pathways cellular response stimulus. stimulus, immune system neutrophil degranulation. There 10 (MYC, LMNA, VCAM1, MAPK6, DDX3X, SHMT2, PHGDH, S100A9, FKBP5 RPS6KA2) by PPI, conclusion, DEGs, relative terms, present investigation might aid understanding provide targets

Language: Английский

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Hantaan virus inhibits type I interferon response by targeting RLR signaling pathways through TRIM25

Virology, Journal Year: 2023, Volume and Issue: 589, P. 109942 - 109942

Published: Nov. 22, 2023

Language: Английский

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