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Global analysis of protein-RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection.

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control its life cycle remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively the cellular and viral RBPs that are involved in SARS-CoV-2 infection. We reveal that SARS-CoV-2 infection profoundly remodels the cellular RNA-bound proteome, which includes wide-ranging effects on RNA metabolic pathways, non-canonical RBPs, and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Among them are several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

SUBMITTER: Kamel W

PROVIDER: S-EPMC8142890 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control SARS-CoV-2 infection remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively which cellular and viral RBPs are involved in SARS-CoV-2 infection. We reveal that the cellular RNA-bound proteome is remodelled upon SARS-CoV-2 infection, having widespread effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

2021-05-29 | GSE171382 | GEO

Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. SARS-CoV-2 relies on cellular RNA-binding proteins (RBPs) to replicate and spread, although which RBPs control SARS-CoV-2 infection remains largely unknown. Here, we employ a multi-omic approach to identify systematically and comprehensively the cellular and viral RBPs that are involved in SARS-CoV-2 infection. We reveal that SARS-CoV-2 infection profoundly remodels the cellular RNA-bound proteome, which includes wide-ranging effects on RNA metabolic pathways, non-canonical RBPs and antiviral factors. Moreover, we apply a new method to identify the proteins that directly interact with viral RNA, uncovering dozens of cellular RBPs and six viral proteins. Amongst them, several components of the tRNA ligase complex, which we show regulate SARS-CoV-2 infection. Furthermore, we discover that available drugs targeting host RBPs that interact with SARS-CoV-2 RNA inhibit infection. Collectively, our results uncover a new universe of host-virus interactions with potential for new antiviral therapies against COVID-19.

2021-09-09 | PXD023418 | Pride

Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection

Project description:Global analysis of protein-RNA interactions in SARS-CoV-2 infected cells reveals key regulators of infection

| PRJNA719366 | ENA

The global succinylation of SARS-CoV-2-infected host cells reveals drug targets.

Project description:SARS-CoV-2, the causative agent of the COVID-19 pandemic, undergoes continuous evolution, highlighting an urgent need for development of novel antiviral therapies. Here we show a quantitative mass spectrometry-based succinylproteomics analysis of SARS-CoV-2 infection in Caco-2 cells, revealing dramatic reshape of succinylation on host and viral proteins. SARS-CoV-2 infection promotes succinylation of several key enzymes in the TCA, leading to inhibition of cellular metabolic pathways. We demonstrated that host protein succinylation is regulated by viral nonstructural protein (NSP14) through interaction with sirtuin 5 (SIRT5); overexpressed SIRT5 can effectively inhibit virus replication. We found succinylation inhibitors possess significant antiviral effects. We also found that SARS-CoV-2 nucleocapsid and membrane proteins underwent succinylation modification, which was conserved in SARS-CoV-2 and its variants. Collectively, our results uncover a regulatory mechanism of host protein posttranslational modification and cellular pathways mediated by SARS-CoV-2, which may become antiviral drug targets against COVID-19.

| S-EPMC9335334 | biostudies-literature

Comparative transcriptome analysis reveals key epigenetic targets in SARS-CoV-2 infection.

Project description:COVID-19 is an infection caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), which has caused a global outbreak. Current research efforts are focused on the understanding of the molecular mechanisms involved in SARS-CoV-2 infection in order to propose drug-based therapeutic options. Transcriptional changes due to epigenetic regulation are key host cell responses to viral infection and have been studied in SARS-CoV and MERS-CoV; however, such changes are not fully described for SARS-CoV-2. In this study, we analyzed multiple transcriptomes obtained from cell lines infected with MERS-CoV, SARS-CoV, and SARS-CoV-2, and from COVID-19 patient-derived samples. Using integrative analyses of gene co-expression networks and de-novo pathway enrichment, we characterize different gene modules and protein pathways enriched with Transcription Factors or Epifactors relevant for SARS-CoV-2 infection. We identified EP300, MOV10, RELA, and TRIM25 as top candidates, and more than 60 additional proteins involved in the epigenetic response during viral infection that has therapeutic potential. Our results show that targeting the epigenetic machinery could be a feasible alternative to treat COVID-19.

| S-EPMC8144203 | biostudies-literature

Transcriptional landscape of circulating platelets from patients with COVID-19 reveals key subnetworks and regulators underlying SARS-CoV-2 infection: implications for immunothrombosis.

Project description:BackgroundThrombosis and coagulopathy are pervasive pathological features of coronavirus disease 2019 (COVID-19), and thrombotic complications are a sign of severe COVID-19 disease and are associated with multiple organ failure and increased mortality. Platelets are essential cells that regulate hemostasis, thrombus formation and inflammation; however, the mechanism underlying the interaction between platelets and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear.ResultsThe present study performed RNA sequencing on the RNA isolated from platelets obtained from 10 COVID-19 patients and eight healthy donors, and discovered that SARS-CoV-2 not only significantly altered the coding and non-coding transcriptional landscape, but also altered the function of the platelets, promoted thrombus formation and affected energy metabolism of platelets. Integrative network biology analysis identified four key subnetworks and 16 risk regulators underlying SARS-CoV-2 infection, involved in coronavirus disease-COVID-19, platelet activation and immune response pathways. Furthermore, four risk genes (upstream binding transcription factor, RNA polymerase II, I and III subunit L, Y-box binding protein 1 and yippee like 2) were found to be associated with COVID-19 severity. Finally, a significant alteration in the von Willebrand factor/glycoprotein Ib-IX-V axis was revealed to be strongly associated with platelet aggregation and immunothrombosis.ConclusionsThe transcriptional landscape and the identification of critical subnetworks and risk genes of platelets provided novel insights into the molecular mechanisms of immunothrombosis in COVID-19 progression, which may pave the way for the development of novel therapeutic strategies for preventing COVID-19-associated thrombosis and improving the clinical outcome of COVID-19 patients.

| S-EPMC8827164 | biostudies-literature

Syncytia formation by SARS-CoV-2 infected cells.

Project description:Severe cases of COVID-19 are associated with extensive lung damage and the presence of infected multinucleated syncytial pneumocytes. The viral and cellular mechanisms regulating the formation of these syncytia are not well understood. Here, we show that SARS-CoV-2 infected cells express the Spike protein (S) at their surface and fuse with ACE2-positive neighbouring cells. Expression of S without any other viral proteins triggers syncytia formation. Interferon-induced transmembrane proteins (IFITMs), a family of restriction factors that block the entry of many viruses, inhibit S-mediated fusion, with IFITM1 being more active than IFITM2 and IFITM3. On the contrary, the TMPRSS2 serine protease, which is known to enhance infectivity of cell-free virions, processes both S and ACE2 and increases syncytia formation by accelerating the fusion process. TMPRSS2 thwarts the antiviral effect of IFITMs. Our results show that SARS-CoV-2 pathological effects are modulated by cellular proteins that either inhibit or facilitate syncytia formation.

| S-SCDT-EMBOJ-2020-106267 | biostudies-other

System-wide profiling of protein-RNA interactions in sindbis infected cells reveals host regulators of infection

Project description:RNA viruses rely on cellular RNA-binding proteins (RBPs) to infect the host cell. However, the repertoire of the cellular RBPs exploited by viruses is largely unknown. Using the ‘RNA interactome capture’ method, we profiled in a proteome-wide scale the RBP-RNA interactions occurring during sindbis virus (SINV) infection. We discover that SINV affects the activity of hundreds of RBPs, essentially rewiring the host RNA-bound proteome. Such alterations do not relate to changes in protein abundance but are rather due to subcellular redistribution of RBPs and pervasive transcriptome remodelling. Strikingly, RBPs stimulated by SINV accumulate in the cytoplasmic compartments where the virus replicates and interact with viral RNA. Perturbation of these RBPs can restrict or promote infection; for example, GEMIN5 binds to key regulatory regions of SINV RNAs and inhibits viral protein expression. Importantly, we show that drug based RBP intervention may have potential as therapeutic strategy against viruses.

2019-02-28 | PXD009789 | Pride

Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies

Project description:Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here we uncover a role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.

| S-SCDT-10_1038-S44318-024-00061-0 | biostudies-other

Integrated interactome and transcriptome analysis reveals key host factors critical for SARS-CoV-2 infection.

Project description:The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has seriously threatened global public health and caused huge economic losses. Omics studies of SARS-CoV-2 can help understand the interaction between the virus and host, thereby providing a new perspective in guiding the intervention and treatment of the SARS-CoV-2 infection. Since large amount of SARS-CoV-2 omics data have been accumulated in public databases, this study aimed to identify key host factors involved in SARS-CoV-2 infection through systematic integration of transcriptome and interactome data. By manually curating published studies, we obtained a comprehensive SARS-CoV-2-human protein-protein interactions (PPIs) network, comprising 3591 human proteins interacting with 31 SARS-CoV-2 viral proteins. Using the RobustRankAggregation method, we identified 123 multiple cell line common genes (CLCGs), of which 115 up-regulated CLCGs showed host enhanced innate immunity and chemotactic response signatures. Combined with network analysis, co-expression and functional enrichment analysis, we discovered four key host factors involved in SARS-CoV-2 infection: IFITM1, SERPINE1, DDX60, and TNFAIP2. Furthermore, SERPINE1 was found to facilitate SARS-CoV-2 replication, and can alleviate the endoplasmic reticulum (ER) stress induced by ORF8 protein through interaction with ORF8. Our findings highlight the importance of systematic integration analysis in understanding SARS-CoV-2-human interactions and provide valuable insights for future research on potential therapeutic targets against SARS-CoV-2 infection.

| S-EPMC10166720 | biostudies-literature

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