Genome-wide characterization of SARS-CoV-2 cytopathogenic proteins in the search of antiviral targets

Zhang, Jiantao; Li, Qi; Cosme, Ruth S. Cruz; Gerzanich, Vladimir; Tang, Qiyi; Simard, J. Marc; Zhao, Yuqi

doi:10.1101/2021.11.23.469747

Cited by 6 publications

(12 citation statements)

References 61 publications

(47 reference statements)

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“…Based on the ORF3a protein structural analysis ( Kern et al, 2021 ), we found a unique diG motif between the anti-parallel β4 and β5 sheets. These two glycine residues are part of a type II β-turn that could potentially be critical in maintaining the protein structure ( Zhang et al, 2022a ). Since the dCR1 deletion covers the diG residues, and we previously showed that deletion of the G188 residue (dG188) significantly enhanced the cytopathic effect of ORF3a ( Zhang et al, 2022a ; Zhang et al, 2022b ), we decided to focus on characterizing the possible role of the diG residues in intracellular transport.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the current literature, the ORF3a (Open-Reading Frame 3a) protein of SARS-CoV-2 could be one of the viral proteins that contribute to COVID-19, as it is well-known for its role in viral pathogenesis and its activities have been linked to cell death and tissue damages ( Ren et al, 2020 ; Silvas et al, 2021 ; Zhang et al, 2022a ; McGrath et al, 2022 ), induction of cytokine storm that is a major cause of COVID-19-related death ( Siu et al, 2019 ; Xu et al, 2022 ) and the severity of COVID-19 ( Issa et al, 2020 ; Majumdar and Niyogi, 2020 ; Lednicky et al, 2021 ; Nagy et al, 2021 ). Furthermore, ORF3a is uniquely shared by SARS-CoV and SARS-CoV-2 within the genus of β-coronaviruses ( Kern et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Even though a number of well conserved functional motifs of ORF3a are linked to various functionalities ( Tan et al, 2004 ; Lu et al, 2006 ; Minakshi and Padhan, 2014 ; Siu et al, 2019 ; Jin et al, 2021 ; Kern et al, 2021 ), the functional relationship of some ORF3a activities with the overall structure of ORF3a protein remains unknown. For instance, we recently showed that ORF3a induces apoptosis and necrosis through the induction of host cellular oxidative stress-mediated reactive oxygen species (ROS) production and NF-κB-mediated pro-inflammatory cytokine productions including TNFα and IL-6 ( Zhang et al, 2022a ), which are two strong and independent survival predictors of the patient with COVID-19 ( Del Valle et al, 2020 ; Sayah et al, 2021 ). Interestingly, a single amino acid deletion at a residue G188 (∆G188) resulted in a marked increase in the ORF3a-induced cytopathic effects ( Zhang et al, 2022a ).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, we recently showed that ORF3a induces apoptosis and necrosis through the induction of host cellular oxidative stress-mediated reactive oxygen species (ROS) production and NF-κB-mediated pro-inflammatory cytokine productions including TNFα and IL-6 ( Zhang et al, 2022a ), which are two strong and independent survival predictors of the patient with COVID-19 ( Del Valle et al, 2020 ; Sayah et al, 2021 ). Interestingly, a single amino acid deletion at a residue G188 (∆G188) resulted in a marked increase in the ORF3a-induced cytopathic effects ( Zhang et al, 2022a ). The region where G188 resides is not in any one of the known functional domains.…”

Section: Introductionmentioning

confidence: 99%

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A novel diG motif in ORF3a protein of SARS-Cov-2 for intracellular transport

Cruz-Cosme

Zhang

Liu

et al. 2022

Front. Cell Dev. Biol.

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The ongoing SARS-CoV-2/COVID-19 pandemic caused a global public health crisis. Yet, everyone’s response to SARS-CoV-2 infection varies, and different viral variants confer diverse pathogenicity. Thus, it is imperative to understand how viral determinants contribute to COVID-19. Viral ORF3a protein is one of those viral determinants, as its functions are linked to induction of cell and tissues damages, disease severity and cytokine storm that is a major cause of COVID-19-related death. ORF3a is a membrane-associated protein. Upon synthesis, it is transported from endoplasmic reticulum, Golgi apparatus to plasma membrane and subcellular endomembranes including endosomes and lysosomes. However, how ORF3a is transported intracellularly remains elusive. The goal of this study was to carry out a systematic mutagenesis study to determine the structural relationship of ORF3a protein with its subcellular locations. Single amino acid (aa) and deletion mutations were generated in the putative function-relevant motifs and other regions of interest. Immunofluorescence and ImageJ analyses were used to determine and quantitate subcellular locations of ORF3a mutants in comparison with wildtype ORF3a. The wildtype ORF3a localizes predominantly (Pearson’s coefficients about 0.8) on the membranes of endosomes and lysosomes. Consistent with earlier findings, deletion of the YXXΦ motif, which is required for protein export, retained ORF3a in the Golgi apparatus. Interestingly, mutations in a double glycine (diG) region (aa 187–188) displayed a similar phenotype to the YXXΦ deletion, implicating a similar role of the diG motif in intracellular transport. Indeed, interrupting any one of the two glycine residues such as deletion of a single (dG188), both (dG187/dG188) or substitution (G188Y) of these residues led to ORF3a retention in the Golgi apparatus (Pearson’s coefficients ≥0.8). Structural analyses further suggest that the diG motif supports a type-II β-turn between the anti-parallel β4 and β5 sheets and connects to the YXXΦ motif via hydrogen bonds between two monomers. The diG- YXXΦ interaction forms a hand-in-hand configuration that could facilitate dimerization. Together, these observations suggest a functional role of the diG motif in intracellular transport of ORF3a.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel diG motif in ORF3a protein of SARS-Cov-2 for intracellular transport

Cruz-Cosme

Zhang

Liu

et al. 2022

Front. Cell Dev. Biol.

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“…Its RNA encodes four major structural proteins, which include spike protein (S), envelope protein (E), membrane protein (M), and nucleocapsid protein (N) (41) [Figure 1]. Besides, 16 nonstructural proteins (NSPs) and 9 accessory proteins are included in the 29 proteins encoded (42).…”

Section: Structure Of Sars-cov-2mentioning

confidence: 99%

Pathogenic Mechanism and Multi-omics Analysis of Oral Manifestations in COVID-19

et al. 2022

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Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease that seriously threatens human life. The clinical manifestations of severe COVID-19 include acute respiratory distress syndrome and multiple organ failure. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, spreads through contaminated droplets. SARS-CoV-2 particles have been detected in the saliva of COVID-19 patients, implying that the virus can infect and damage the oral cavity. The oral manifestations of COVID-19 include xerostomia and gustatory dysfunction. Numerous studies showed that the four structural proteins of SARS-CoV-2 are its potential pathogenic factors, especially the S protein, which binds to human ACE2 receptors facilitating the entry of the virus into the host cells. Usually, upon entry into the host cell, a pathogen triggers the host’s immune response. However, a mount of multi-omics and immunological analyses revealed that COVID-19 is caused by immune dysregulation. A decrease in the number and phenotypes of immune cells, IFN-1 production and excessive release of certain cytokines have also been reported. In conclusion, this review summarizes the oral manifestations of COVID-19 and multi-omics analysis of SARS-CoV-2 infection.

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What do we know about the function of SARS-CoV-2 proteins?

Justo Arevalo,

Castillo-Chávez,

Uribe Calampa

et al. 2023

Front. Immunol.

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The COVID-19 pandemic has highlighted the importance in the understanding of the biology of SARS-CoV-2. After more than two years since the first report of COVID-19, it remains crucial to continue studying how SARS-CoV-2 proteins interact with the host metabolism to cause COVID-19. In this review, we summarize the findings regarding the functions of the 16 non-structural, 6 accessory and 4 structural SARS-CoV-2 proteins. We place less emphasis on the spike protein, which has been the subject of several recent reviews. Furthermore, comprehensive reviews about COVID-19 therapeutic have been also published. Therefore, we do not delve into details on these topics; instead we direct the readers to those other reviews. To avoid confusions with what we know about proteins from other coronaviruses, we exclusively report findings that have been experimentally confirmed in SARS-CoV-2. We have identified host mechanisms that appear to be the primary targets of SARS-CoV-2 proteins, including gene expression and immune response pathways such as ribosome translation, JAK/STAT, RIG-1/MDA5 and NF-kβ pathways. Additionally, we emphasize the multiple functions exhibited by SARS-CoV-2 proteins, along with the limited information available for some of these proteins. Our aim with this review is to assist researchers and contribute to the ongoing comprehension of SARS-CoV-2’s pathogenesis.

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Genome-wide characterization of SARS-CoV-2 cytopathogenic proteins in the search of antiviral targets

Cited by 6 publications

References 61 publications

A novel diG motif in ORF3a protein of SARS-Cov-2 for intracellular transport

A novel diG motif in ORF3a protein of SARS-Cov-2 for intracellular transport

Pathogenic Mechanism and Multi-omics Analysis of Oral Manifestations in COVID-19

What do we know about the function of SARS-CoV-2 proteins?

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