EGR1 functions as a new host restriction factor for SARS-CoV-2 to inhibit virus replication through the E3 ubiquitin ligase MARCH8

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(10)

Published: Sept. 29, 2023

Emerging vaccine-breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight an urgent need for novel antiviral therapies. Understanding the pathogenesis of coronaviruses is critical developing drugs. Here, we demonstrate that SARS-CoV-2 N protein suppresses interferon (IFN) responses by reducing early growth response gene-1 (EGR1) expression. The overexpression EGR1 inhibits replication promoting IFN-regulated expression, which interacts with and degrades via E3 ubiquitin ligase MARCH8 cargo receptor NDP52. mutants without activity are no longer able to degrade proteins, indicating proteins dependent on its activity. This study found a immune evasion mechanism utilized protein, helpful understanding guiding design new prevention strategies against emerging coronaviruses.

Language: Английский

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Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(3), P. 879 - 889

Published: Feb. 22, 2024

The highly infectious coronavirus SARS-CoV-2 relies on the viral main protease (Mpro, also known as 3CLpro or Nsp5) to proteolytically process polyproteins encoded by genome for release of functional units in host cells initiate replication. Mpro interacts with proteins innate immune pathways, such IRF3 and STAT1, suppress their activities facilitate virus survival proliferation. To identify mechanism regulating Mpro, we screened various classes E3 ubiquitin ligases found that Parkin RING-between-RING family can induce ubiquitination degradation cell. Furthermore, when undergo mitophagy, PINK1 kinase activates enhances Mpro. We elevated expression significantly decreased replication virus. Interestingly, infection downregulates mouse lung tissues compared healthy controls. These results suggest an antiviral role a ligase targeting potential exploiting virus–host interaction mediated treat infection.

Language: Английский

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The emerging roles of MARCH8 in viral infections: A double-edged Sword

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(9), P. e1011619 - e1011619

Published: Sept. 14, 2023

The host cell membrane-associated RING-CH 8 protein (MARCH8), a member of the E3 ubiquitin ligase family, regulates intracellular turnover many transmembrane proteins and shows potent antiviral activities. Generally, 2 modes are performed by MARCH8. On one hand, MARCH8 catalyzes viral envelope glycoproteins (VEGs) ubiquitination thus leads to their degradation, which is cytoplasmic tail (CT)-dependent (CTD) mode. other traps VEGs at some compartments (such as trans-Golgi network, TGN) but without inducing tail-independent (CTI) mode, hijacks furin, cellular proprotein convertase, block cleavage. In addition, C-terminal tyrosine-based motif (TBM) 222YxxL225 also plays key role in its CTI effects. contrast potency, occasionally hijacked viruses bacteria enhance invasion, indicating duplex pathogenic infections. This review summarizes MARCH8's roles how evade restriction, shedding light on novel therapeutic avenues.

Language: Английский

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Deubiquitinase USP39 promotes SARS-CoV-2 replication by deubiquitinating and stabilizing the envelope protein

Antiviral Research, Journal Year: 2023, Volume and Issue: 221, P. 105790 - 105790

Published: Dec. 27, 2023

The SARS-CoV-2 envelope (E) protein is highly conserved among different viral variants and important for assembly production. Our recent study found that the E ubiquitinated degraded by E3 ligase RNF5 through proteasome pathway. However, whether ubiquitination can be reversed host deubiquitinase has not yet been determined. Here, we identify mass spectrum analysis deubiquitinases USP14 USP39 specifically interact with E, while potently reverses polyubiquitination. interacts via arginine-rich motif (AR) deubiquitinates polyubiquitination inactive ubiquitin-specific protease domain. Therefore, protects from RNF5-mediated degradation, resulting in enhancement of stability E-induced cytokine storms. Moreover, loss-and-gain assays demonstrated promotes replication various strains stabilizing level but other proteins. findings provide useful targets development novel anti-SARS-CoV-2 strategies.

Language: Английский

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Modulation of Lymphotoxin β Surface Expression by Kaposi's Sarcoma‐Associated Herpesvirus K3 Through Glycosylation Interference

Journal of Medical Virology, Journal Year: 2025, Volume and Issue: 97(1)

Published: Jan. 1, 2025

ABSTRACT Kaposi's sarcoma‐associated herpesvirus (KSHV) employs diverse mechanisms to subvert host immune responses, contributing its infection and pathogenicity. As an evasion strategy, KSHV encodes the Membrane‐Associated RING‐CH (MARCH)‐family E3 ligases, K3, K5, which target remove several regulators from cell surface. In this study, we investigate impact of K3 K5 on lymphotoxin receptor (LTβR) ligands, LTβ LIGHT, are type II transmembrane proteins function as pivotal mediators during virus infection. Upon co‐expression viral MARCH with LTβR showed that selectively targeted LTβ, but not for downregulation surface expression. Specifically, ligases interacted domain LTβ. Intriguingly, immature form whereas fully mature form. Subsequent biochemical analyses revealed disrupted initial steps N‐glycosylation maturation This interference resulted in sequestration within endoplasmic reticulum, impeding trafficking plasma membrane. Consequently, K3‐mediated expression suppressed downstream signaling pathway. These findings uncover a novel mechanism by ligase inhibits membrane pathway inflammatory ligand through glycosylation interference, potentially evading LTβR‐mediated antiviral immunity.

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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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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Dual roles of CXCR4 (C-X-C motif chemokine receptor 4) in promoting entry of ebolavirus and targeting excessive glycoprotein for reticulophagic degradation to facilitate viral fitness.

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

Published: April 13, 2025

Ebola virus disease (EVD) caused by Zaire Ebolavirus (EBOV) infection is a major threat to public health in Africa and even worldwide, due its extremely high mortality rate. However, there are still no effective antiviral therapies that can completely cure EVD. A comprehensive understanding of virus-host interactions would be beneficial for developing new agents. Here, we showed CXCR4-induced macroautophagy/autophagy was internalized endosomes interacting with glycoprotein (GP) on viral particles during EBOV infection; this promoted the attachment entry, which reduced CXCR4 antagonist neutralizing antibody. We also found increased replication downregulating cytotoxic GP promote fitness instead influencing assembly factory. Mechanistically, excessive could hijack sorting transporting pathways their HGS, one key components ESCRT machinery; subsequently carried back endoplasmic reticulum CXCR4, where E3 ubiquitin ligase RNF185 recruited polyubiquitinate K27- K63-linked manner. Finally, polyubiquitinated degraded lysosomes via reticulophagy RETREG1 (reticulophagy regulator 1), an ATG3- ATG5-dependent Our findings revealed dual roles regulation life cycle, either acting as entry factor facilitate or targeting reticulophagic degradation, providing evidence hijacked host vesicular transportation system through efficient fitness.

Language: Английский

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miR-603 Mediates Thyroid Cancer Progression by Inhibiting HACE1-Dependent YAP1 Degradation

Archives of Biochemistry and Biophysics, Journal Year: 2025, Volume and Issue: unknown, P. 110453 - 110453

Published: May 1, 2025

Language: Английский

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Non-antibiotic therapies for multidrug-resistant gastrointestinal infections: an overview of the use of probiotics, natural compounds, and bacteriophages

Frontiers in Antibiotics, Journal Year: 2025, Volume and Issue: 4

Published: May 6, 2025

The worldwide increasing frequency and severity of multidrug-resistant gastrointestinal (MDR-GI) infections not only raises awareness the debilities conventional antibiotic treatments but also highlights demand for alternative interventions. One these alternatives is probiotics, harmless bacteria that compete with pathogenic species, which have been considered beneficial due to their therapeutic potential since they strengthen mucosal barrier modulate host immune response. Other natural compounds (e.g., polyphenols, flavonoids, essential oils) present diverse antimicrobial mechanisms, are promising mitigate resistant pathogens. Finally, bacteriophages, viruses target specific bacteria, constitute a precise approach in MDR lysed or disrupted by biofilms formed during colonization without compromising normal gut microbiome. Therefore, manuscript provides an integrated perspective on non-antibiotic therapies manage MDR-GI infections; this purpose, it covers aspects such as action current clinical applications, challenges limit broader application practice. combining approaches personalizing infection adjusted patients’ microbiome profiles discussed, aiming enhance efficacy reduce resistance risks. importance continued research development optimize debated, addressing need surpass regulatory barriers conducting large-scale trials establish safety alternatives. This overview knowledge contributes ongoing efforts develop sustainable strategies combat global burden resistance.

Language: Английский

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