Human OAS1 activation is highly dependent on both RNA sequence and context of activating RNA motifs

Schwartz, Samantha L.; Park, Esther N.; Vachon, Virginia K.; Danzy, Shamika; Conn, Graeme L.

doi:10.1093/nar/gkaa513

Cited by 30 publications

(38 citation statements)

References 60 publications

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“…OAS1 is an oligoadenylate synthetase enzyme that binds dsRNA and changes conformation to generate oligoadenylates and activate RNase L to digest RNA. 92,93 It has also been proposed that OAS1 may have RNase-independent roles. 29,30 OAS1 is expressed by multiple cell types in the myeloid lineage including monocytes, macrophages, and microglia, as well as natural killer cell lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene

Magusali

Graham

Piers

et al. 2021

Brain

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Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer’s disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer’s disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer’s disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer’s disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression.

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Section: Discussionmentioning

confidence: 99%

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene

Magusali

Graham

Piers

et al. 2021

Brain

View full text Add to dashboard Cite

show abstract

“…The data presented here provide support for OAS1 linking AD and critical illness with COVID-19 by controlling the pro-inflammatory output of myeloid cells. OAS1 is an oligoadenylate synthetase enzyme that binds dsRNA and changes conformation to generate oligoadenylates and activate RNase L to digest RNA (Schwartz and Conn, 2019;Schwartz et al, 2020). It has also been proposed that OAS1 may also have RNase-independent roles (Kristiansen et al, 2010;Li et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Genetic variability associated withOAS1expression in myeloid cells increases the risk of Alzheimer’s disease and severe COVID-19 outcomes

Magusali

et al. 2021

Preprint

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Genome-wide association studies of late-onset Alzheimer’s disease (AD) have highlighted the importance of variants associated with genes expressed by the innate immune system in determining risk for AD. Recently, we and others have shown that genes associated with variants that confer risk for AD are significantly enriched in transcriptional networks expressed by amyloid-responsive microglia. This allowed us to predict new risk genes for AD, including the interferon-responsive oligoadenylate synthetase 1 (OAS1). However, the function of OAS1 within microglia and its genetic pathway are not known. Using genotyping from 1,313 individuals with sporadic AD and 1,234 control individuals, we confirm that the OAS1 variant, rs1131454, is associated with increased risk for AD and decreased OAS1 expression. Moreover, we note that the same locus was recently associated with critical illness in response to COVID-19, linking variants that are associated with AD and a severe response to COVID-19. By analysing single-cell RNA-sequencing (scRNA-seq) data of isolated microglia from APPNL-G-F knock-in and wild-type C57BL/6J mice, we identify a transcriptional network that is significantly upregulated with age and amyloid deposition, and contains the mouse orthologue Oas1a, providing evidence that Oas1a plays an age-dependent function in the innate immune system. We identify a similar interferon-related transcriptional network containing OAS1 by analysing scRNA-seq data from human microglia isolated from individuals with AD. Finally, using human iPSC-derived microglial cells (h-iPSC-Mg), we see that OAS1 is required to limit the pro-inflammatory response of microglia. When stimulated with interferon-gamma (IFN-γ), we note that cells with lower OAS1 expression show an exaggerated pro-inflammatory response, with increased expression and secretion of TNF-α. Collectively, our data support a link between genetic risk for AD and susceptibility to critical illness with COVID-19 centred on OAS1 and interferon signalling, a finding with potential implications for future treatments of both AD and COVID-19, and the development of biomarkers to track disease progression.

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“…OAS1 is a member of OAS family which acts as antiviral enzymes induced by interferon. It was reported that neutrophils, which contribute to tumor metastasis through multiple pathways, were the top tumor immune infiltrating cell type associated with OAS in in breast cancer [ 35 ]. CDH1 deletions have been shown to cause cancers with immune cell infiltration, activation of targetable immune checkpoint pathways and gene expression related to T-regulatory (Treg) cell signaling [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel immune microenvironment signature predicting survival and therapeutic options for bladder cancer

Yan

Huang

Cai

et al. 2020

Aging

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Few studies have investigated the potential of tumor immune microenvironment genes as indicators of urinary bladder cancer. Here, we sought to establish an immune-related gene signature for determining prognosis and treatment options. We developed a ten-gene tumor immune microenvironment signature and evaluated its prognostic capacity on internal and external cohorts. Multivariate Cox regression and nomogram analyses revealed the prognostic risk model as an independent and effective indicator of prognosis. We observed lower proportions of CD8+ T cells, dendritic cells, regulatory T cells, higher proportions of macrophages and neutrophils in high UBC risk group. UBC tissues with high-risk score tend to exhibit high TP53 and RB1 mutation rates, high PD1/PD-L1 expression and poor-survival basal squamous subtypes, while those with low-risk score tend to have high FGFR3 mutation rates and luminal papillary subtypes. Unexpectedly, we found a highly significant positive correlation between glycolytic genes and risk score, highlighting metabolic competition in tumor ecosystem and potential therapeutic avenues. Our study thus revealed a tumor immune microenvironment signature for predicting prognostic and response to immune checkpoint inhibitors against bladder cancer. Prospective studies are required to further test the predictive capacity of this model.

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Human OAS1 activation is highly dependent on both RNA sequence and context of activating RNA motifs

Cited by 30 publications

References 60 publications

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene

Genetic variability associated withOAS1expression in myeloid cells increases the risk of Alzheimer’s disease and severe COVID-19 outcomes

Identification of a novel immune microenvironment signature predicting survival and therapeutic options for bladder cancer

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