OAS1

Official Full Name

2'-5'-oligoadenylate synthetase 1

Organism

Homo sapiens

GeneID

4938

Background

This interferon-induced gene encodes a protein that synthesizes 2',5'-oligoadenylates (2-5As). This protein plays a key role in innate cellular antiviral response, and has been implicated in other cellular processes like cell growth and apoptosis. Alternative splicing results in multiple transcript variants with different enzymatic activities. Polymorphisms in this gene have been associated with susceptibility to viral infection, including SARS-CoV-2, and diabetes mellitus, type 1. This gene is located in a cluster of related genes on chromosome 12. [provided by RefSeq, May 2022]

Synonyms

OIAS; IFI-4; OIASI; IMD100; E18/E16;

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Detailed Information

The 2’-5’ oligoadenylate synthetase (OAS1) enzyme demonstrates pro-apoptotic and anti-proliferative properties. IFN regulated OAS1 appears to be the rate-limiting enzyme in RNaseL activity and its generation of an effective inflammatory response. OAS1 is induced by both type I and type II INFs and as an integral part of the acute inflammatory/innate immunity pathway, it is required for an effective anti-viral response. Studies have also shown that OAS1 negatively regulates proliferation. OAS1, in the presence of double-stranded RNA structures, such as viral genomes or single-stranded RNA transcripts with double-stranded character, converts ATP to a series of unusual 2’-5’–phosphodiester linked oligoadenylates or 2-5A [(A2’p9)n A or 2-5A for short]. 2-5A in turn is required for the activation of RNaseL.

Genetic variations caused by single-nucleotide polymorphisms (SNPs) are of particular interest due to their ability to classify tumors and identify therapeutic targets required in the description of the genetic changes underlying cancer. Overall there are more than 50 polymorphic markers known to exist in the OAS1 gene. Those of interest are splice site polymorphisms (rs10774671) and polymorphisms that are non-synonymous, rs1131467, rs1051042 and rs2660. Two of these polymorphic markers (rs1131467 (exon C) and rs2660) are well studied and demonstrate the association with various diseases.

OAS1 and autoimmune diseases

The OAS1 gene locus and its polymorphisms have demonstrated increased susceptibility to an array of autoimmune diseases. A study conducted by O'Brien M. et al. confirmed splice acceptor site SNP rs10774671 AA genotype with conferred susceptibility to multiple sclerosis (MS) and the GG genotype protected against increased disease activity contributing to MS. Additionally, Faedetz M et al. showed haplotypic association of the G allele at rs10774671 and the A allele at rs3741981 with the susceptibility to MS.17 Rs10774671 has also been linked to type I diabetes (T1D) a disease characterized as autoimmune destruction of the pancreatic beta-cells. Susceptibility to Sjögren's syndrome (SS), a disease that causes an immune defense against healthy cells that produce saliva and tears causing dryness of the mouth and eyes, has been shown to be influenced by rs10774671 which was confirmed through meta-analysis of two independent cohorts (Figure 1). Most recently the OAS1 gene locus was significantly up-regulated among individuals with type 2 diabetes (T2D) and T2D related infections. Once characterized as metabolic disease in comparison to T1D it has been shown that susceptibility to T2D is influenced by tumor necrosis factor-α inflammation caused by the presence of fatty tissue, influenced by the OAS1/RNaseL pathway, which increases the level of fatty acids in the blood leading to fatty liver disease, high blood pressure, high cholesterol and significantly increased insulin resistance in the body. Lastly, a study of systemic lupus erythematosus (SLE), a chronic autoimmune disease with multiple organ involvement, in which auto-antibodies induce tissue damage, identified OAS1 as 1 of 10 common marker genes associated with SLE.

Figure 1. Results of genetic association analyses in OAS1 region. (Li H, et al., PLoS Genet 2017)

OAS1 and infectious diseases

The importance of OAS1 proteins in the human antiviral response is highlighted by genetic studies designating it as an antiviral enzyme. Variations of OAS1 SNPs, specifically rs10774671, have shown that they can confer increased susceptibility to influenza A, hepatitis C, flavivirus, West Nile virus, respiratory epithelial cell syncytial virus, ocular herpes simplex virus type 1, SARS, Human enterovirus 71 (EV71) and coxsackievirus (hand, foot and mouth disease). OAS1 polymorphism rs2285934 has also been associated with the severity of liver disease in HIV/HCV-co-infected patients, suggesting a significant role in the progression of hepatic fibrosis. OAS1 SNP rs1131476 is associated with chronic hepatitis B (CHB) and hepatitis B e antigen-negative chronic hepatitis B. The most notable of viral association with OAS1 polymorphisms is with increased viral persistence of Human Papilloma Virus (HPV), which has been linked to cervical cancer and in some cases prostate cancer.

OAS1 and cancer

IFN induced apoptosis is dependent on OAS1 expression and requires functional BRCA1 and STAT1 in breast cancer cells. Inhibition of OAS1 by siRNA in NIH/3T3 fibroblasts induces a metastatic phenotype such as anchorage-independent cell growth. Ectopic OAS1 expression results in increased anti-viral activity and growth suppression in a glioblastoma cell line (T98G) and growth arrest and differentiation in myeloid cells. OAS1 polymorphisms have been linked to cervical intraepithelial neoplasia grade 3 (CIN3), the direct precursor of cervical cancer. Thus, OAS1 itself could act as a pro-differentiation, pro-apoptotic and anti-proliferative protein.

References:

Liu X, et al. A functional variant in the OAS1 gene is associated with Sjögren's syndrome complicated with HBV infection. Scientific Reports, 2017, 7(1):17571.
Li H, et al. Identification: of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. Plos Genetics, 2017, 13(6):e1006820.
O'Brien M, et al. OAS1: a multiple sclerosis susceptibility gene that influences disease severity. Neurology, 2010, 75(5):411-8.
Thavachelvam K, et al. Rapid Uptake and Inhibition of Viral Propagation by Extracellular OAS1. J Interferon Cytokine Res, 2014, 35(5).
Joseph C G, et al. Association of the Autoimmune Disease Scleroderma with an Immunologic Response to Cancer. Science, 2014, 343(6167):152.

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