Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection

Iida, Kei; Ajiro, Masahiko; Muramoto, Yukiko; Takenaga, Toru; Denawa, Masatsugu; Kurosawa, Ryo; Noda, Takeshi

doi:10.1101/2021.08.23.457314

Cited by 4 publications

(2 citation statements)

References 32 publications

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“…We failed at detecting cell-type specificity of the protective isoform p46 (Zhou et al 2021), which exhibited broad expression across all organs and was among the most highly expressed isoforms alongside p42.The least expressed isoform, p44-b, was responsible for only around 10% of the total OAS1 expression. This is in line with numerous studies consistently showing that amplifying the p44-b isoform by qPCR is difficult due to its very low or undetectable expression level (Noguchi et al 2013;Iida et al 2021). Interestingly, we found that this trend was reversed in testis, with p44b accounting for almost 60% of total OAS1 expression and being the predominant isoform (Figure 2D).…”

Section: Oas1 Isoform Cell-type Specificitysupporting

confidence: 91%

A human commons cell atlas reveals cell type specificity for OAS1 isoforms

Galvez-Merchán,

Booeshaghi,

Pachter

2024

Preprint

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We describe an open source Human Commons Cell Atlas comprising 2.9 million cells across 27 tissues that can be easily updated and that is structured to facilitate custom analyses. To showcase the flexibility of the atlas, we demonstrate that it can be used to study isoforms of genes at cell resolution. In particular, we study cell type specificity of isoforms of OAS1, which has been shown to offer SARS-CoV-2 protection in certain individuals that display higher expression of the p46 isoform. Using our commons cell atlas we localize the OAS1 p44b isoform to the testis, and find that it is specific to round and elongating spermatids. By virtue of enabling customized analyses via a modular and dynamic atlas structure, the commons cell atlas should be useful for exploratory analyses that are intractable within the rigid framework of current gene-centric cell atlases.

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Section: Oas1 Isoform Cell-type Specificitysupporting

confidence: 91%

A human commons cell atlas reveals cell type specificity for OAS1 isoforms

Galvez-Merchán,

Booeshaghi,

Pachter

2024

Preprint

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“…Upregulation of the p46 splice variant of OAS1 has been associated with protection against severe COVID-19 (Huffman et al 2022). Production of the p46 variant is contingent upon a G allele for SNP rs10774671 whereas Calu-3 cells are homozygous A (Iida et al 2021) and therefore cannot express the p46 variant. It follows that, if the reduced viral replication we observed in Calu-3 cells expressing low levels of EXOSC2 is mediated via OAS protein upregulation, then it must be achieved only through OAS3 and not OAS1.…”

Section: Discussionmentioning

confidence: 99%

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

Moll

Odon

Harvey

et al. 2022

Preprint

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New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Genome-wide association studies (GWAS) have identified risk loci, but some loci are associated with co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins; EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. Lung-specific eQTLs were identified from GTEx (v7) for each of the 332 host proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed an association between increased expression of EXOSC2 and higher risk of clinical COVID-19 which survived stringent multiple testing correction. EXOSC2 is a component of the RNA exosome and indeed, LC-MS/MS analysis of protein pulldowns demonstrated an interaction between the SARS-CoV-2 RNA polymerase and the majority of human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu-3 cells reduced EXOSC2 protein expression, impeded SARS-CoV-2 replication and upregulated oligoadenylate synthase (OAS) genes, which have been linked to a successful immune response against SARS-CoV-2. Reduced EXOSC2 expression did not reduce cellular viability. OAS gene expression changes occurred independent of infection and in the absence of significant upregulation of other interferon-stimulated genes (ISGs). Targeted depletion or functional inhibition of EXOSC2 may be a safe and effective strategy to protect at-risk individuals against clinical COVID-19.

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Optimization of 5′UTR to evade SARS-CoV-2 Nonstructural protein 1-directed inhibition of protein synthesis in cells

Chen

Chang

et al. 2023

Appl Microbiol Biotechnol

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Maximizing the expression level of therapeutic proteins in cells is the general goal for DNA/mRNA therapies. It is particularly challenging to achieve efficient protein expression in the cellular contexts with inhibited translation machineries, such as in the presence of cellular Nonstructural protein 1 (Nsp1) of coronaviruses (CoVs) that has been reported to inhibit overall protein synthesis of host genes and exogenously delivered mRNAs/DNAs. In this study, we thoroughly examined the sequence and structure contexts of viral and non-viral 5′UTRs that determine the protein expression levels of exogenously delivered DNAs and mRNAs in cells expressing SARS-CoV-2 Nsp1. It was found that high 5′-proximal A/U content promotes an escape from Nsp1-directed inhibition of protein synthesis and results in selective protein expression. Furthermore, 5′-proximal Cs were found to significantly enhance the protein expression in an Nsp1-dependent manner, while Gs located at a specific window close to the 5′-end counteract such enhancement. The distinct protein expression levels resulted from different 5′UTRs were found correlated to Nsp1-induced mRNA degradations. These findings ultimately enabled rational designs for optimized 5′UTRs that lead to strong expression of exogenous proteins regardless of the translationally repressive Nsp1. On the other hand, we have also identified several 5′-proximal sequences derived from host genes that are capable of mediating the escapes. These results provided novel perspectives to the optimizations of 5′UTRs for DNA/mRNA therapies and/or vaccinations, as well as shedding light on the potential host escapees from Nsp1-directed translational shutoffs. Key points • The 5′-proximal SL1 and 5a/b derived from SARS-CoV-2 genomic RNA promote exogenous protein synthesis in cells expressing Nsp1 comparing with non-specific 5′UTRs. • Specific 5′-proximal sequence contexts are the key determinants of the escapes from Nsp1-directed translational repression and thereby enhance protein expressions. • Systematic mutagenesis identified optimized 5′UTRs that strongly enhance protein expression and promote resistance to Nsp1-induced translational repression and RNA degradation. Supplementary Information The online version contains supplementary material available at 10.1007/s00253-023-12442-2.

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Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection

Cited by 4 publications

References 32 publications

A human commons cell atlas reveals cell type specificity for OAS1 isoforms

A human commons cell atlas reveals cell type specificity for OAS1 isoforms

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

Optimization of 5′UTR to evade SARS-CoV-2 Nonstructural protein 1-directed inhibition of protein synthesis in cells

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