Integration of Omics Data and Network Models to Unveil Negative Aspects of SARS-CoV-2, from Pathogenic Mechanisms to Drug Repurposing DOI Creative Commons
Letizia Bernardo, Andrea Lomagno, Pierluigi Mauri

et al.

Biology, Journal Year: 2023, Volume and Issue: 12(9), P. 1196 - 1196

Published: Aug. 31, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the COVID-19 health emergency, affecting and killing millions of people worldwide. Following SARS-CoV-2 infection, patients show a spectrum symptoms ranging from asymptomatic to very severe manifestations. In particular, bronchial pulmonary cells, involved at initial stage, trigger hyper-inflammation phase, damaging wide range organs, including heart, brain, liver, intestine kidney. Due urgent need for solutions limit virus’ spread, most efforts were initially devoted mapping outbreak trajectories variant emergence, as well rapid search effective therapeutic strategies. Samples collected hospitalized or dead early stages pandemic have been analyzed over time, date they still represent an invaluable source information shed light on molecular mechanisms underlying organ/tissue damage, knowledge which could offer new opportunities diagnostics designs. For these purposes, in combination with clinical data, omics profiles network models play key role providing holistic view pathways, processes functions affected by viral infection. fact, addition epidemiological networks are being increasingly adopted integration multiomics recently their use has expanded identification drug targets repositioning existing drugs. These topics will be covered here exploring landscape survey-based studies using systems biology approaches derived paying particular attention those that considered samples human origin.

Language: Английский

Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity DOI Creative Commons
Zemin Yang, Bryan A. Johnson, Victoria Meliopoulos

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113965 - 113965

Published: March 1, 2024

G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits assembly and interacts with via an ITFG motif, residue F17, the N protein. Prior studies examining impact G3PB1-N interaction on SARS-CoV-2 replication have produced inconsistent findings, role this pathogenesis is unknown. Here, we use structural biochemical analyses define residues required for G3BP1-N structure-guided mutagenesis selectively disrupt interaction. We find N-F17A mutation causes highly specific loss G3BP1/2. fails inhibit cells, has decreased replication, pathology vivo. Further mechanistic indicate N-F17-mediated promotes infection by limiting sequestration genomic RNA (gRNA) into granules.

Language: Английский

Citations

25
The E3 ligase TRIM22 restricts SARS-CoV-2 replication by promoting proteasomal degradation of NSP8 DOI Creative Commons
Lujie Fan, Yuzheng Zhou,

Xiafei Wei

et al.

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

Published: Jan. 26, 2024

Non-structural proteins (NSPs) play a crucial role in the replication of severe acute respiratory syndrome coronavirus 2, facilitating virus amplification and propagation. In this study, we conducted comprehensive investigation into stability all subunits comprising RNA-dependent RNA polymerase complex. Notably, our results reveal for first time that NSP8 is relatively unstable protein, which found to be readily recognized degraded by proteasome. This degradation process mediated host E3 ligase tripartite motif containing 22 (TRIM22), also member interferon stimulated gene (ISG) family. Our study elucidates novel mechanism antiviral effect TRIM22, utilizes its own ubiquitin activity hinder viral inducing ubiquitination subsequent NSP8. These findings provide new ideas development therapeutic strategies. addition, conserved property raises possibility developing broad drugs targeting TRIM22-NSP8 interaction.

Language: Английский

Citations

18
Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration DOI Creative Commons
Elena Gavilán, Rafael Medina-Guzman, Bazhena Bahatyrevich-Kharitonik

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 123 - 123

Published: Jan. 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.

Language: Английский

Citations

12
CRL4B E3 ligase recruited by PRPF19 inhibits SARS-CoV-2 infection by targeting ORF6 for ubiquitin-dependent degradation DOI Creative Commons

Linran Zhang,

Pengfei Hao, Xiang Chen

et al.

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

Citations

11
Mutations accumulated in the Spike of SARS-CoV-2 Omicron allow for more efficient counteraction of the restriction factor BST2/Tetherin DOI Creative Commons
Yuhang Shi, Sydney Simpson,

Yuexuan Chen

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(1), P. e1011912 - e1011912

Published: Jan. 8, 2024

BST2/Tetherin is a restriction factor with broad antiviral activity against enveloped viruses, including coronaviruses. Specifically, BST2 traps nascent particles to membrane compartments, preventing their release and spread. In turn, viruses have evolved multiple mechanisms counteract BST2. Here, we examined the interactions between SARS-CoV-2. Our study shows that reduces SARS-CoV-2 virion release. However, virus uses Spike (S) protein downregulate This requires physical interaction S BST2, which routes for lysosomal degradation in Clathtin- ubiquitination-dependent manner. By surveying different variants of concern (Alpha-Omicron), found Omicron more efficient at counteracting mutations account its enhanced anti-BST2 activity. Mapping analyses revealed several surfaces extracellular region are required an Spike, variant has changed patterns association improve counteraction. Therefore, our suggests that, besides enhancing receptor binding evasion neutralizing antibodies, accumulated afford counteraction highlights antagonism important infectivity

Language: Английский

Citations

7
SARS-CoV-2 protein ORF8 limits expression levels of Spike antigen and facilitates immune evasion of infected host cells DOI Creative Commons
Ik-Jung Kim, Yong‐ho Lee, Mir M. Khalid

et al.

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(8), P. 104955 - 104955

Published: June 24, 2023

Recovery from COVID-19 depends on the ability of host to effectively neutralize virions and infected cells, a process largely driven by antibody-mediated immunity. However, with newly emerging variants that evade Spike-targeting antibodies, re-infections breakthrough infections are increasingly common. A full characterization severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mechanisms counteracting immunity is therefore needed. Here, we report ORF8 virally encoded SARS-CoV-2 factor controls cellular Spike antigen levels. We show limits availability mature inhibiting protein synthesis retaining at endoplasmic reticulum, reducing cell-surface levels recognition anti-SARS-CoV-2 antibodies. In conditions limited availability, found restricts incorporation during viral assembly, in virions. Cell entry these then leaves fewer molecules cell surface, limiting antibody cells. Based findings, propose may adopt an ORF8-dependent strategy facilitates immune evasion cells for extended production.

Language: Английский

Citations

16
LLPS of FXR proteins drives replication organelle clustering for β-coronaviral proliferation DOI Creative Commons
Meng Li, Ya-li Hou, Yuzheng Zhou

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(6)

Published: April 8, 2024

β-Coronaviruses remodel host endomembranes to form double-membrane vesicles (DMVs) as replication organelles (ROs) that provide a shielded microenvironment for viral RNA synthesis in infected cells. DMVs are clustered, but the molecular underpinnings and pathophysiological functions remain unknown. Here, we reveal fragile X–related (FXR) family proteins (FXR1/FXR2/FMR1) required DMV clustering induced by expression of non-structural (Nsps) Nsp3 Nsp4. Depleting FXRs results dispersion cytoplasm. FXR1/2 FMR1 recruited sites via specific interaction with Nsp3. condensates driven liquid–liquid phase separation, which is clustering. FXR1 liquid droplets concentrate Nsp3-decorated liposomes vitro. FXR facilitate recruitment translation machinery efficient surrounding DMVs. In cells depleted FXRs, SARS-CoV-2 significantly attenuated. Thus, exploits cluster separation replication.

Language: Английский

Citations

6
A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication DOI Creative Commons
Yuzheng Zhou,

Zongpeng Chen,

Sijie Liu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: June 27, 2024

Abstract The ORF9b protein, derived from the nucleocapsid’s open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting innate response. Despite its significance, precise regulatory mechanisms underlying function remain elusive. In present study, we unveil that of including emerging mutant strains like Delta Omicron, can undergo ubiquitination at K67 site subsequent degradation via proteasome pathway, despite certain mutations among these strains. Moreover, our investigation further uncovers pivotal role translocase outer mitochondrial membrane 70 (TOM70) a substrate receptor, bridging with heat shock 90 alpha (HSP90α) Cullin 5 (CUL5) to form complex. Within this complex, CUL5 triggers ORF9b, acting host antiviral factor, while HSP90α functions stabilize it. Notably, treatment HSP90 inhibitors such GA or 17-AAG accelerates leading pronounced inhibition SARS-CoV-2 replication. Single-cell sequencing data revealed up-regulation lung epithelial cells COVID-19 patients, suggesting potential mechanism which may exploit evade immunity. Our study identifies CUL5-TOM70-HSP90α complex critical regulator stability, shedding light on intricate host–virus response dynamics offering promising avenues drug development against clinical settings.

Language: Английский

Citations

6
Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication DOI Creative Commons
Li Zhou, Ruochuan Liu,

Heather Pathak

et al.

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

Citations

5
Deubiquitinase USP39 promotes SARS-CoV-2 replication by deubiquitinating and stabilizing the envelope protein DOI Creative Commons
Xiang Chen, Tian Li,

Linran Zhang

et al.

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

Citations

11