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A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation

ABSTRACT: Long-range RNA-RNA pairing impacts the genome structure and function of SARS-CoV-2 variants. To understand structure and function relationships of different SARS-CoV-2 variants that have emerged during the COVID-19 pandemic, we performed high throughput structure probing and modelling of the genomic structures of the wildtype (WT), Alpha, Beta, Delta and Omicron variants of the SARS-CoV-2. We observed that genomes of SARS-CoV-2 variants are generally structurally conserved, and that single nucleotide variations (SNVs) and interactions with RNA binding proteins (RBPs) can impact RNA structures across the viruses. Importantly, using proximity ligation sequencing, we identified many conserved ultra-long-range RNA-RNA interactions, including one that spans more than 17kb in both the WT virus and Omicron variant. We showed that mutations that disrupt this 17kb long-range interacting structure reduce virus fitness at late stages of its infection cycle, while compensatory mutations partially restore virus fitness. Additionally, we showed that this ultra-long-range RNA-RNA interaction binds directly to ADAR1 to alter the RNA editing levels on the viral genome. These studies deepen our understanding of RNA structures in SARS-CoV-2 genome and their ability to interact with host factors to facilitate virus infectivity.

ORGANISM(S): Chlorocebus Sabaeus

SUBMITTER: Wan Yue

PROVIDER: PXD065815 | JPOST Repository | Wed Jul 30 00:00:00 BST 2025

REPOSITORIES: jPOST

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			Action	DRS
	20250411_S10_Teth_1_S1-B7_1_6638.d.7z	Other
	20250411_S10_Teth_1_S1-B7_1_6638.d.quant	Other
	20250411_S11_Teth_2_S1-B8_1_6639.d.7z	Other
	20250411_S11_Teth_2_S1-B8_1_6639.d.quant	Other
	20250411_S12_Teth_3_S1-B9_1_6640.d.7z	Other

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A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation [dataset2]

Project description:Various SARS-CoV-2 viruses have caused the COVID-19 pandemic world-wide. As the viruses evolve different mutations along their genomes, these mutations can impact virus RNA structures and their phenotypes. Here we probe the RNA structures across Wuhan, alpha, beta, delta and omnicron strains of the SARS-CoV-2 viruses. We observe that while the mutations impact RNA structures, it is not the main source of RNA structure changes (RBPs?). Structurally conserved structures are enriched for both long and short RNA pair-wise interactions. We identified a conserved 17kb long range interaction that decreases the virus fitness when mutated. Additionally, this interaction binds to ADAR1 to alter editing levels on the virus. These studies reveal the importance of RNA structures along virus genomes to facilitate virus infectivity.

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A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation [dataset1]

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A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation [SPLASH]

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RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2

Project description:SARS-CoV-2, the virus behind the deadly COVID-19 pandemic, continues to spread globally even as vaccine strategies are proving effective in preventing hospitalizations and deaths. However, evolving variants of the virus appear to be more transmissive and vaccine efficacy towards them is waning. As a result, SARS-CoV-2 will continue to have a deadly impact on public health into the foreseeable future. One strategy to bypass the continuing problem of newer variants is to target host proteins required for viral replication. We have used this host-targeted antiviral (HTA) strategy that targets DDX3, a host DEAD-box RNA helicase that is usurped by SARS-CoV-2 for virus production. We demonstrated that targeting DDX3 with RK-33, a small molecule inhibitor, reduced the viral load in four isolates of SARS-CoV-2 (Lineage A, and Lineage B Alpha, Beta, and Delta variants) by one to three log orders in Calu-3 cells. Furthermore, proteomics and RNA-seq analyses indicated that most SARS-CoV-2 genes were downregulated by RK-33 treatment. Also, we show that the use of RK-33 decreases TMPRSS2 expression, which may be due to DDX3s ability to unwind G-quadraplex structures present in the TMPRSS2 promoter. The data presented supports the use of RK-33 as an HTA strategy to control SARS-CoV-2 infection, irrespective of its mutational status, in humans.

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