The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Feb. 3, 2023

Abstract The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2) has a global health crisis; its structural protein envelope (E) is critical for viral entry, budding, production, and induction of pathology which makes it potential target therapeutics against COVID-19. Here, we find that the E3 ligase RNF5 interacts with catalyzes ubiquitination E on 63rd lysine, leading to degradation ubiquitin-proteasome system (UPS). Importantly, RNF5-induced inhibits SARS-CoV-2 replication pharmacological activator Analog-1 alleviates development in mouse infection model. We also found distinctively expressed different age groups patients displaying severity, may be exploited as prognostic marker Furthermore, recognized from various strains SARS-CoV, suggesting targeting broad-spectrum antiviral strategy. Our findings provide novel insights into role UPS antagonizing replication, opens new avenues therapeutic intervention combat COVID-19 pandemic.

Language: Английский

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Multiomics approach reveals the ubiquitination-specific processes hijacked by SARS-CoV-2

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 7, 2022

Abstract The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is a global pandemic that seriously threatens health and socioeconomic development, but the existed antiviral drugs vaccines still cannot yet halt spread of epidemic. Therefore, comprehensive profound understanding pathogenesis SARS-CoV-2 urgently needed to explore effective therapeutic targets. Here, we conducted multiomics study SARS-CoV-2-infected lung epithelial cells, including transcriptomic, proteomic, ubiquitinomic. Multiomics analysis showed cells activated strong innate immune response, interferon inflammatory responses. Ubiquitinomic further reveals underlying mechanism disrupting host response. In addition, proteins were found be ubiquitinated during infection despite fact itself didn’t code any E3 ligase, ubiquitination at three sites on Spike protein could significantly enhance viral infection. Further screening ubiquitin ligases deubiquitinating enzymes (DUBs) library revealed four influencing infection, thus providing several new This combined with high-throughput not only modulates immunity, also promotes hijacking ubiquitination-specific processes, highlighting potential anti-inflammation

Language: Английский

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Human MARCH1, 2, and 8 block Ebola virus envelope glycoprotein cleavage via targeting furin P domain

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(2)

Published: Feb. 1, 2024

Abstract Membrane‐associated RING‐CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes. Previous work showed that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates MARCH1 and MARCH2 share a similar pattern in restricting EBOV GP‐pseudotyped infection. Human retain GP at the trans ‐Golgi network, reduce its cell surface display, impair virions infectivity. Furthermore, we uncover host proprotein convertase furin could interact with MARCH1/2 intracellularly. Importantly, P domain is verified be recognized by MARCH1/2/8, which critical for their blocking activities. Besides, bovine murine also proteolytic processing. Altogether, our findings confirm of different mammalian origins relatively conserved feature cleavage, provide clues subsequent MARCHs antiviral studies may facilitate development novel strategies antagonize enveloped

Language: Английский

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CRL4B E3 ligase recruited by PRPF19 inhibits SARS-CoV-2 infection by targeting ORF6 for ubiquitin-dependent degradation

mBio, Journal Year: 2024, Volume and Issue: 15(2)

Published: Jan. 24, 2024

The cellular biological function of the ubiquitin-proteasome pathway as an important modulator for regulation many fundamental processes has been greatly appreciated. critical role in viral pathogenesis become increasingly apparent. It is a powerful tool that host cells use to defend against infection. Some proteins can restriction factors limit infection by ubiquitin-dependent degradation. In this research, we identificated CUL4B-DDB1-PRPF19 E3 Ubiquitin Ligase Complex mediate proteasomal degradation ORF6, leading inhibition replication. Moreover, CUL4B activator etoposide alleviates disease development mouse model, suggesting agent or its derivatives may be used treat infections caused SARS-CoV-2. We believe these results will extremely useful scientific and clinic communities their search cues preventive measures combat COVID-19 pandemic.

Language: Английский

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Palmitoylation of SARS‐CoV‐2 S protein is critical for S‐mediated syncytia formation and virus entry

Journal of Medical Virology, Journal Year: 2021, Volume and Issue: 94(1), P. 342 - 348

Published: Sept. 16, 2021

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the cause of ongoing disease 2019 (COVID‐19) pandemic. The S protein key viral for associating with ACE2, receptor SARS‐CoV‐2. There are many kinds posttranslational modifications in protein. However, detailed mechanism palmitoylation SARS‐CoV‐2 remains to be elucidated. In our current study, we characterized S. Both C15 and cytoplasmic tail were palmitoylated. Fatty acid synthase inhibitor C75 zinc finger DHHC domain‐containing palmitoyltransferase (ZDHHC) 2‐BP reduced Interestingly, was not required plasma membrane targeting but critical S‐mediated syncytia formation pseudovirus particle entry. Overexpression ZDHHC2, ZDHHC3, ZDHHC4, ZDHHC5, ZDHHC8, ZDHHC9, ZDHHC11, ZDHHC14, ZDHHC16, ZDHHC19, ZDHHC20 promoted Furthermore, those ZDHHCs identified associate Our study only reveals also will shed important light into role virus

Language: Английский

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Host antiviral factors hijack furin to block SARS-CoV-2, ebola virus, and HIV-1 glycoproteins cleavage

Emerging Microbes & Infections, Journal Year: 2023, Volume and Issue: 12(1)

Published: Jan. 2, 2023

Viral envelope glycoproteins are crucial for viral infections. In the process of enveloped viruses budding and release from producer cells, presented on membrane surface as spikes, promoting virus's next-round infection target cells. However, host cells evolve counteracting mechanisms in long-term virus-host co-evolutionary processes. For instance, cell antiviral factors could potently suppress replication by targeting their through multiple channels, including intracellular synthesis, glycosylation modification, assembly into virions, binding to receptors. Recently, a group studies discovered that some proteins specifically recognized proprotein convertase (PC) furin blocked its cleavage glycoproteins, thus impairing infectivity. Here, this review, we briefly summarize several such analyze roles reducing aiming at providing insights future studies.

Language: Английский

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Restriction of Viral Glycoprotein Maturation by Cellular Protease Inhibitors

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 332 - 332

Published: Feb. 22, 2024

The human genome is estimated to encode more than 500 proteases performing a wide range of important physiological functions. They digest proteins in our food, determine the activity hormones, induce cell death and regulate blood clotting, for example. During viral infection, however, some can switch sides activate glycoproteins, allowing entry virions into new target cells spread infection. To reduce unwanted effects, multiple protease inhibitors proteolytic processing self non-self proteins. This review summarizes current knowledge endogenous inhibitors, which are known limit replication by interfering with activation glycoproteins. We describe underlying molecular mechanisms highlight diverse strategies virion infectivity. also provide examples how viruses evade restriction imposed inhibitors. Finally, we briefly outline cellular be modified exploited therapeutic purposes. In summary, this aims summarize understanding as components immune response variety pathogens.

Language: Английский

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MARCH8 Targets Cytoplasmic Lysine Residues of Various Viral Envelope Glycoproteins

Microbiology Spectrum, Journal Year: 2022, Volume and Issue: 10(1)

Published: Jan. 12, 2022

A member of the MARCH E3 ubiquitin ligase family, MARCH8, downregulates many different kinds host transmembrane proteins, resulting in regulation cellular homeostasis. On other hands, MARCH8 acts as an antiviral factor when it binds to and HIV-1 envelope glycoprotein vesicular stomatitis virus G-glycoprotein that are viral proteins.

Language: Английский

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Pseudotyped Vesicular Stomatitis Virus-Severe Acute Respiratory Syndrome-Coronavirus-2 Spike for the Study of Variants, Vaccines, and Therapeutics Against Coronavirus Disease 2019

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 12

Published: Jan. 14, 2022

World Health Organization (WHO) has prioritized the infectious emerging diseases such as Coronavirus Disease (COVID-19) in terms of research and development effective tests, vaccines, antivirals, other treatments. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), etiological causative agent COVID-19, is a virus belonging to risk group 3 that requires Biosafety Level (BSL)-3 laboratories corresponding facilities for handling. An alternative these BSL-3/-4 use pseudotyped can be handled BSL-2 laboratory study purposes. Recombinant Vesicular Stomatitis Virus (VSV) generated with complementary DNA from complete negative-stranded genomic RNA, deleted G glycoprotein and, instead, incorporation fusion protein, like SARS-CoV-2 Spike (S protein). Accordingly, it called VSV-SARS-CoV-2 S. In this review, we have described generation VSV focus on optimization application The pseudovirus been addressed by its neutralizing antibody assays order evaluate new vaccine, emergent variants (delta omicron), approved vaccine efficacy against concern well viral fusion-focused treatment analysis performed under conditions.

Language: Английский

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Advances in HIV-1 Assembly

Viruses, Journal Year: 2022, Volume and Issue: 14(3), P. 478 - 478

Published: Feb. 26, 2022

The assembly of HIV-1 particles is a concerted and dynamic process that takes place on the plasma membrane infected cells. An abundance recent discoveries has advanced our understanding complex sequence events leading to particle assembly, budding, release. Structural studies have illuminated key features maturation, including dramatic structural transition occurs between immature Gag lattice formation mature viral capsid core. critical role inositol hexakisphosphate (IP6) in both been elucidated. basis for selective packaging genomic RNA into virions revealed. This review will provide an overview process, with focus advances field, point out areas where questions remain can benefit from future investigation.

Language: Английский

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