scholarly journals Structural analysis of viral ExoN domains reveals polyphyletic hijacking events

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0246981
Author(s):  
Adrián Cruz-González ◽  
Israel Muñoz-Velasco ◽  
Wolfgang Cottom-Salas ◽  
Arturo Becerra ◽  
José A. Campillo-Balderas ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Zinc Fingers ◽  
Viral Proteins ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Structural Homology ◽  
Innate Immune Signaling ◽  
Conservation Level ◽  
High Conservation ◽  
Domain Exon

Nidoviruses and arenaviruses are the only known RNA viruses encoding a 3’-5’ exonuclease domain (ExoN). The proofreading activity of the ExoN domain has played a key role in the growth of nidoviral genomes, while in arenaviruses this domain partakes in the suppression of the host innate immune signaling. Sequence and structural homology analyses suggest that these proteins have been hijacked from cellular hosts many times. Analysis of the available nidoviral ExoN sequences reveals a high conservation level comparable to that of the viral RNA-dependent RNA polymerases (RdRp), which are the most conserved viral proteins. Two highly preserved zinc fingers are present in all nidoviral exonucleases, while in the arenaviral protein only one zinc finger can be identified. This is in sharp contrast with the reported lack of zinc fingers in cellular ExoNs, and opens the possibility of therapeutic strategies in the struggle against COVID-19.

scholarly journals Structural analysis of viral ExoN domains reveals polyphyletic hijacking events

2021 ◽  
Author(s):  
A. Cruz-González ◽  
I. Muñoz-Velasco ◽  
W. Cottom-Salas ◽  
A. Becerra ◽  
J.A. Campillo-Balderas ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Zinc Fingers ◽  
Viral Proteins ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Structural Homology ◽  
Innate Immune Signaling ◽  
Conservation Level ◽  
High Conservation ◽  
Domain Exon

AbstractNidoviruses and arenaviruses are the only known RNA viruses encoding a 3’-5’ exonuclease domain (ExoN). The proofreading activity of the ExoN domain has played a key role in the growth of nidoviral genomes, while in arenaviruses this domain partakes in the suppression of the host innate immune signaling. Sequence and structural homology analyses suggest that these proteins have been hijacked from cellular hosts many times. Analysis of the available nidoviral ExoN sequences reveals a high conservation level comparable to that of the viral RNA-dependent RNA polymerases (RdRp), which are the most conserved viral proteins. Two highly preserved zinc fingers are present in all nidoviral exonucleases, while in the arenaviral protein only one zinc finger can be identified. This is in sharp contrast with the reported lack of zinc fingers in cellular ExoNs, and opens the possibility of therapeutic strategies in the struggle against COVID-19.

scholarly journals Distinct RIG-I and MDA5 Signaling by RNA Viruses in Innate Immunity

2007 ◽  
Vol 82 (1) ◽  
pp. 335-345 ◽  
Author(s):  
Yueh-Ming Loo ◽  
Jamie Fornek ◽  
Nanette Crochet ◽  
Gagan Bajwa ◽  
Olivia Perwitasari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Rna Viruses ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Influenza B ◽  
Immune Signaling ◽  
Innate Immune Signaling

ABSTRACT Alpha/beta interferon immune defenses are essential for resistance to viruses and can be triggered through the actions of the cytoplasmic helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Signaling by each is initiated by the recognition of viral products such as RNA and occurs through downstream interaction with the IPS-1 adaptor protein. We directly compared the innate immune signaling requirements of representative viruses of the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Reoviridae for RIG-I, MDA5, and interferon promoter-stimulating factor 1 (IPS-1). In cultured fibroblasts, IPS-1 was essential for innate immune signaling of downstream interferon regulatory factor 3 activation and interferon-stimulated gene expression, but the requirements for RIG-I and MDA5 were variable. Each was individually dispensable for signaling triggered by reovirus and dengue virus, whereas RIG-I was essential for signaling by influenza A virus, influenza B virus, and human respiratory syncytial virus. Functional genomics analyses identified cellular genes triggered during influenza A virus infection whose expression was strictly dependent on RIG-I and which are involved in processes of innate or adaptive immunity, apoptosis, cytokine signaling, and inflammation associated with the host response to contemporary and pandemic strains of influenza virus. These results define IPS-1-dependent signaling as an essential feature of host immunity to RNA virus infection. Our observations further demonstrate differential and redundant roles for RIG-I and MDA5 in pathogen recognition and innate immune signaling that may reflect unique and shared biologic properties of RNA viruses whose differential triggering and control of gene expression may impact pathogenesis and infection.

scholarly journals The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

2021 ◽  
Author(s):  
Jordan M Meyers ◽  
Muthukumar Ramanathan ◽  
Ronald L Shanderson ◽  
Laura Donohue ◽  
Ian Ferguson ◽  
...  
Keyword(s):  
Protein Translation ◽  
Viral Proteins ◽  
Innate Immune ◽  
Host Protein ◽  
Host Proteins ◽  
Immune Signaling ◽  
Data Resource ◽  
Regulatory Variants ◽  
Innate Immune Signaling ◽  
Human Proteins

AbstractViral proteins localize within subcellular compartments to subvert host machinery and promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This identified viral proteins at specific intracellular locations, such as association of accessary proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate immune signaling, ER-Golgi transport, and protein translation. It identified viral protein adjacency to specific host proteins whose regulatory variants are linked to COVID-19 severity, including the TRIM4 interferon signaling regulator which was found proximal to the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was associated with inhibited host protein translation whereas ORF6 localization with MAVS was associated with inhibited RIG-I 2CARD-mediated IFNB1 promoter activation. Quantitative proteomics identified candidate host targets for the NSP5 protease, with specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data resource identifies host factors proximal to viral proteins in living human cells and nominates pathogenic mechanisms employed by SARS-CoV-2.Author SummarySARS-CoV-2 is the latest pathogenic coronavirus to emerge as a public health threat. We create a database of proximal host proteins to 17 SARS-CoV-2 viral proteins. We validate that NSP1 is proximal to the EIF3 translation initiation complex and is a potent inhibitor of translation. We also identify ORF6 antagonism of RNA-mediate innate immune signaling. We produce a database of potential host targets of the viral protease NSP5, and create a fluorescence-based assay to screen cleavage of peptide sequences. We believe that this data will be useful for identifying roles for many of the uncharacterized SARS-CoV-2 proteins and provide insights into the pathogenicity of new or emerging coronaviruses.

SARS-CoV-2 Biology Insights, Part I. Genome-wide structure and druggability: literature review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Side Effects ◽  
Literature Review ◽  
Host Cell ◽  
Nucleoside Analogs ◽  
Viral Proteins ◽  
Therapeutic Strategies ◽  
Adverse Side Effects ◽  
Viral Proteases ◽  
Genome Wide ◽  
Therapeutic Alternatives

BACKGROUND COVID-19 pandemic prompts the study of coronavirus biology and search of putative therapeutic strategies. OBJECTIVE To compare SARS-CoV-2 genome-wide structure and proteins with other coronaviruses, focusing on putative coronavirus-specific or SARS-CoV-2 specific therapeutic designs. METHODS The genome-wide structure of SARS-CoV-2 was compared to that of SARS and other coronaviruses in order to gain insights, doing a literature review through Google searches. RESULTS There are promising therapeutic alternatives. Host cell targets could be modulated to hamper viral replication, but targeting viral proteins directly would be a better therapeutic design, since fewer adverse side effects would be expected. CONCLUSIONS Therapeutic strategies (Figure 1) could include the modulation of host targets (PARPs, kinases) , competition with G-quadruplexes or nucleoside analogs to hamper RDRP. The nicest anti-CoV options include inhibitors of the conserved essential viral proteases and drugs that interfere ribosome slippage at the -1 PRF site.

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