SARS-CoV-2 and the Host Cell: A Tale of Interactions

Frontiers in Virology, Год журнала: 2022, Номер 1

Опубликована: Янв. 12, 2022

The ability of a virus to spread between individuals, its replication capacity and the clinical course infection are macroscopic consequences multifaceted molecular interaction viral components with host cell. heavy impact COVID-19 on world population, economics sanitary systems calls for therapeutic prophylactic solutions that require deep characterization interactions occurring cells. Unveiling how SARS-CoV-2 engages factors throughout life cycle is therefore fundamental understand pathogenic mechanisms underlying design antiviral therapies strategies. Two years into pandemic, this review provides an overview interplay cell, focus machinery compartments pivotal cellular response. Starting cell surface, following replicative through entry pathways, survival in cytoplasm, egress from infected unravels complex network highlighting knowledge has potential set basis development innovative

Язык: Английский

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The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Ноя. 14, 2022

Язык: Английский

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Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2022, Номер 1868(10), С. 166484 - 166484

Опубликована: Июль 8, 2022

Язык: Английский

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SARS-CoV-2 accessory protein ORF8 is secreted extracellularly as a glycoprotein homodimer

Journal of Biological Chemistry, Год журнала: 2022, Номер 298(3), С. 101724 - 101724

Опубликована: Фев. 11, 2022

ORF8 is an accessory protein encoded by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Consensus regarding the biological functions of lacking, largely because fundamental characteristics this in cells have not been determined. To clarify these features, we herein established expression system 293T cells. Using system, approximately 41% expressed were secreted extracellularly as a glycoprotein homodimer with inter/intramolecular disulfide bonds. Intracellular was sensitive to glycosidase Endo H, whereas portion Endo-H-resistant, suggesting that secretion occurs via conventional pathway. Additionally, immunoblotting analysis showed total amounts major histocompatibility complex class Ι (MHC-I), angiotensin-converting enzyme (ACE2), and SARS-CoV-2 spike (CoV-2 S) proteins coexpressed changed increased expression, although FACS revealed cell surface MHC-I protein, but ACE2 CoV-2 S proteins, reduced expression. Finally, demonstrate RNA-seq had no significant stimulatory effects human primary monocyte-derived macrophages (MDMs). Taken together, our results provide evidence acts homodimer, its are likely associated intracellular transport and/or extracellular signaling infection.

Язык: Английский

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SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

Viruses, Год журнала: 2023, Номер 15(4), С. 871 - 871

Опубликована: Март 29, 2023

The COVID-19 pandemic has resulted in upwards of 6.8 million deaths over the past three years, and frequent emergence variants continues to strain global health. Although vaccines have greatly helped mitigate disease severity, SARS-CoV-2 is likely remain endemic, making it critical understand its viral mechanisms contributing pathogenesis discover new antiviral therapeutics. To efficiently infect, this virus uses a diverse set strategies evade host immunity, accounting for high pathogenicity rapid spread throughout pandemic. Behind some these evasion accessory protein Open Reading Frame 8 (ORF8), which gained recognition due hypervariability, secretory property, unique structure. This review discusses current knowledge on ORF8 proposes actualized functional models describing pivotal roles both replication immune evasion. A better understanding ORF8’s interactions with factors expected reveal essential pathogenic utilized by inspire development novel therapeutics improve outcomes.

Язык: Английский

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Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration

Cells, Год журнала: 2024, Номер 13(2), С. 123 - 123

Опубликована: Янв. 9, 2024

The COVID-19 pandemic has brought to the forefront intricate relationship between SARS-CoV-2 and its impact on neurological complications, including potential links neurodegenerative processes, characterized by a dysfunction of protein quality control systems ER stress. This review article explores role systems, such as Unfolded Protein Response (UPR), Endoplasmic Reticulum-Associated Degradation (ERAD), Ubiquitin–Proteasome System (UPS), autophagy molecular chaperones, in infection. Our hypothesis suggests that produces stress exploits leading disruption proteostasis cannot be solved host cell. culminates cell death may represent link neurodegeneration.

Язык: Английский

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Ubiquitination of SARS-CoV-2 NSP6 and ORF7a Facilitates NF-κB Activation

mBio, Год журнала: 2022, Номер 13(4)

Опубликована: Июль 20, 2022

Patients with severe coronavirus disease 2019 tend to have high levels of proinflammatory cytokines, which eventually lead cytokine storm and the development acute respiratory distress syndrome. However, detailed molecular mechanisms production remain unknown. Here, we screened syndrome 2 (SARS-CoV-2) genes found that nonstructural protein 6 (NSP6) open reading frame 7a (ORF7a) activated NF-κB pathway. NSP6 ORF7a interacted transforming growth factor β-activated kinase 1 (TAK1), knockout (KO) TAK1 or essential modulator (NEMO) abolished activation by ORF7a. Interestingly, K61 was conjugated K63-linked polyubiquitin chains E3 ubiquitin ligase tripartite motif-containing 13, this polyubiquitination appeared crucial for recruitment NEMO NSP6-TAK1 complex activation. On other hand, ring finger 121 (RNF121) required Knockdown RNF121 significantly decreased binding NEMO, resulting in suppression Taken together, our results provide novel insights into pathogenesis SARS-CoV-2 host immune response infection. IMPORTANCE The basis induction cytokines chemokines is unclear, although such clearly related severity COVID-19. show through associations TAK1. TRIM13 RNF121, respectively, appears These suggest inhibition gene products may reduce COVID-19 symptoms decreasing levels.

Язык: Английский

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Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism

Emerging Microbes & Infections, Год журнала: 2023, Номер 12(1)

Опубликована: Апрель 28, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve after its emergence. Given importance in viral infection and vaccine development, mutations the Spike gene have been studied extensively; however, impact of outside are poorly understood. Here, we report that a triple deletion (ΔSGF or ΔLSG) nonstructural protein 6 (nsp6) independently acquired Alpha Omicron sublineages SARS-CoV-2 augments nsp6-mediated antagonism type-I interferon (IFN-I) signaling. Specifically, these deletions enhance ability mutant nsp6 suppress phosphorylation STAT1 STAT2. A parental USA-WA1/2020 strain containing ΔSGF (ΔSGF-WA1) shows reduced susceptibility IFN-I treatment vitro, outcompetes human primary airway cultures, increases virulence mice; ΔSGF-WA1 virus is less virulent than variant (which has additional other genes). Analyses host responses from ΔSGF-WA1-infected mice cultures reveal activation pathways indicative cytokine storm. These results provide evidence affect virus-host interactions may alter pathogenesis variants humans.

Язык: Английский

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Tetherin antagonism by SARS‐CoV‐2 ORF3a and spike protein enhances virus release

EMBO Reports, Год журнала: 2023, Номер 24(12)

Опубликована: Окт. 11, 2023

Язык: Английский

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Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2

Molecular Cell, Год журнала: 2023, Номер 83(14), С. 2559 - 2577.e8

Опубликована: Июль 1, 2023

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remodels the endoplasmic reticulum (ER) to form replication organelles, leading ER stress and unfolded protein response (UPR). However, role of specific UPR pathways in infection remains unclear. Here, we found that SARS-CoV-2 causes marginal activation signaling sensor IRE1α its phosphorylation, clustering dense ER-membrane rearrangements with embedded membrane openings, XBP1 splicing. By investigating factors regulated by IRE1α-XBP1 during infection, identified stress-activated kinase NUAK2 as a novel host-dependency factor for SARS-CoV-2, HCoV-229E, MERS-CoV entry. Reducing abundance or activity impaired particle binding internalization decreasing cell surface levels viral receptors trafficking likely modulating actin cytoskeleton. IRE1α-dependent were elevated SARS-CoV-2-infected bystander non-infected cells, promoting spread maintaining ACE2 facilitating virion cells.

Язык: Английский

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