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      Targeting Nup358/RanBP2 by a viral protein disrupts stress granule formation

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          Abstract

          Viruses have evolved mechanisms to modulate cellular pathways to facilitate infection. One such pathway is the formation of stress granules (SG), which are ribonucleoprotein complexes that assemble during translation inhibition following cellular stress. Inhibition of SG assembly has been observed under numerous virus infections across species, suggesting a conserved fundamental viral strategy. However, the significance of SG modulation during virus infection is not fully understood. The 1A protein encoded by the model dicistrovirus, Cricket paralysis virus (CrPV), is a multifunctional protein that can bind to and degrade Ago-2 in an E3 ubiquitin ligase-dependent manner to block the antiviral RNA interference pathway and inhibit SG formation. Moreover, the R146 residue of 1A is necessary for SG inhibition and CrPV infection in both Drosophila S2 cells and adult flies. Here, we uncoupled CrPV-1A’s functions and provide insight into its underlying mechanism for SG inhibition. CrPV-1A mediated inhibition of SGs requires the E3 ubiquitin-ligase binding domain and the R146 residue, but not the Ago-2 binding domain. Wild-type but not mutant CrPV-1A R146A localizes to the nuclear membrane which correlates with nuclear enrichment of poly(A)+ RNA. Transcriptome changes in CrPV-infected cells are dependent on the R146 residue. Finally, Nup358/RanBP2 is targeted and degraded in CrPV-infected cells in an R146-dependent manner and the depletion of Nup358 blocks SG formation. We propose that CrPV utilizes a multiprong strategy whereby the CrPV-1A protein interferes with a nuclear event that contributes to SG inhibition in order to promote infection.

          Author summary

          Viruses often inhibit a cellular stress response that leads to the accumulation of RNA and protein condensates called stress granules. How this occurs and why this would benefit virus infection are not fully understood. Here, we reveal a viral protein that can block stress granules and identify a key amino acid residue in the protein that inactivates this function. We demonstrate that this viral protein has multiple functions to modulate nuclear events including mRNA export and transcription to regulate stress granule formation. We identify a key host protein that is important for viral protein-mediated stress granule inhibition, thus providing mechanistic insights. This study reveals a novel viral strategy in modulating stress granule formation to promote virus infection.

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          Cytoscape: a software environment for integrated models of biomolecular interaction networks.

          Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.
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            Salmon: fast and bias-aware quantification of transcript expression using dual-phase inference

            We introduce Salmon, a method for quantifying transcript abundance from RNA-seq reads that is accurate and fast. Salmon is the first transcriptome-wide quantifier to correct for fragment GC content bias, which we demonstrate substantially improves the accuracy of abundance estimates and the reliability of subsequent differential expression analysis. Salmon combines a new dual-phase parallel inference algorithm and feature-rich bias models with an ultra-fast read mapping procedure.
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              ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks

              Summary: We have developed ClueGO, an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways and creates a functionally organized GO/pathway term network. It can analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms. A one-click update option allows ClueGO to automatically download the most recent GO/KEGG release at any time. ClueGO provides an intuitive representation of the analysis results and can be optionally used in conjunction with the GOlorize plug-in. Availability: http://www.ici.upmc.fr/cluego/cluegoDownload.shtml Contact: jerome.galon@crc.jussieu.fr Supplementary information: Supplementary data are available at Bioinformatics online.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                PLOS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                1 December 2022
                December 2022
                : 18
                : 12
                : e1010598
                Affiliations
                [1 ] Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
                [2 ] Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America
                Colorado State U., UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0003-0523-8467
                Article
                PPATHOGENS-D-22-00904
                10.1371/journal.ppat.1010598
                9746944
                36455064
                f71dd855-ffd6-40fd-9dc3-354d87b69248
                © 2022 Sadasivan et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 May 2022
                : 17 November 2022
                Page count
                Figures: 10, Tables: 0, Pages: 31
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: PJT-178342
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000038, Natural Sciences and Engineering Research Council of Canada;
                Award ID: RGPIN-2017-04515
                Award Recipient :
                Funded by: National Institutes of Health
                Award ID: A132131 - R01AI137471
                Award Recipient :
                This study was supported by Canadian Institute of Health Research operating grant (PJT-178342) https://cihr-irsc.gc.ca/e/193.html to EJ; Natural Sciences and Engineering Research Council of Canada Discovery grant (RGPIN-2017-04515) https://www.nserc-crsng.gc.ca/index_eng.asp to EJ; National Institutes of Health (A132131 - R01AI137471) https://www.nih.gov/ to RA and SERB-UBC Doctoral scholarship to JS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Transfection
                Research and Analysis Methods
                Molecular Biology Techniques
                Transfection
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
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                Drosophila Melanogaster
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                Animal Studies
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                Biology and life sciences
                Biochemistry
                Nucleic acids
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                Genetics
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                Custom metadata
                vor-update-to-uncorrected-proof
                2022-12-13
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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