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OAS1: The Cost of Host Defense

by Bellbrook Labs / Monday, 13 June 2022 / Published in Emerging Targets, HTS Assays, Innate Immunity, Products
OAS1 The Cost of Host Defense

OAS1 (Oligoadenylate synthetase 1) is induced by type 1 interferon signaling. It recognizes 18 bp (or longer) double stranded RNA segments from invading viruses in the cytosol and catalyzes the production of 2’-5’ linked oligoadenylate (2-5A) from ATP. The 2-5A then, at the expense of yet more ATP, exclusively activates endoribonclease L (RNase L) by inducing its dimerization. The active dimeric RNase L degrades both viral and host single stranded RNA, inhibiting viral replication and even causing the death of infected cells.1

This is a crucial component in innate immunity against infection. Hypomorphic variants invariably leave hosts susceptible to infection. However, gain of function variants and splice isoforms are revealing the cost of harboring a powerful weapon when it is not strictly controlled. Across species, OAS1 seems to be retained only when there is a constant threat of microbial invaders. If it is no longer needed, longevity and fecundity improve.2

OAS1 as a Staunch Defender

Single nucleotide polymorphisms in OAS1 that result in lower 2-5A levels have been found to cause susceptibility to West Nile virus, Hepatitis C virus, and tuberculosis. A variant is also implicated in Sjoegren Syndrome, an autoimmune disease associated with Epstein Barr virus and cytomegalovirus infection. Most recently, a Neanderthal OAS1 isoform, found in people of European descent, produced greater circulating levels of wild type OAS1.  As a consequence, it confers lower susceptibility to COVID-19 and reduces the severity of infection, if it does occur. An intact OAS1/RNase L axis has even been found essential in effecting cancer cell death after the administration of DNA damaging agents.3

OAS1 as a Smoldering Fire

For all the protection OAS1 affords, it factors a cost. When induced, OAS1 causes rampant cellular RNA disruption. Surprisingly, this rampage seems to spare innate immunity mRNAs, encoding interferons and interferon-stimulated gene products. This results in selective expression of innate immunity genes while severely curtailing the expression of metabolic and housekeeping genes. A positive feedback loop can easily arise, stoking an unchecked inflammatory immune response. This phenomenon is now associated with type 1 diabetes, multiple sclerosis, and prostate cancer.1

Recently, patients have been identified with an autoinflammatory immunodeficiency syndrome, characterized by recurrent fever, dermatitis, inflammatory bowel disease, alveolar proteinosis, and hypogammaglobulinemia. De novo OAS1 gain of function variants were responsible for the corresponding impairment and death of systemic monocytes, macrophages, and B cells. Each of these different variants was enzymatically active in the absence of any RNA provocation. Once interferon induction occurred, the OAS/RNase L axis proceeded on its own and became self-perpetuating through its selective RNA degradation.4

While OAS1 can be a fierce and able defender, it also has the potential to simultaneously impair immunity and create an inflammatory storm.

Learn More About The Transcreener OAS Assay

References:

1.  Schwartz, S.L. et al. (2020) Human OAS1 Activation is Highly Dependent on Both RNA Sequence and Context of Activating RNA Motifs. Nucleic Acids Research, 48(13), 7520-7531. https://doi.org/10.1093/nar/gkaa513

2.  Carey, C. M. et al. (2019) Recurrent Loss-of-Function Mutations Reveal Costs to OAS1 Antiviral Activity in Primates. Cell Host & Microbe, 25, 336-343. https://doi.org/10.1016/j.chom.2019.01.001

3.  Zhou, S. et al. (2021) A Neanderthal OAS1 Isoform Protects Individuals of European Ancestry Against COVID-19 Susceptibility and Severity. Nature Medicine, 27, 659-667. https://doi.org/10.1038/s41591-021-01281-1

4.  Magg, T. et al. (2021) Heterozygous OAS1 Gain-of-Function Variants Cause an Autoinflammatory Immunodeficiency. Science Immunology, 6(60), 1-30. https://doi.org/10.1126/sciimmunol.abf9564

Tagged under: Innate Immunity, OAS1, Transcreener OAS Assay

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