Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses
Open accessAbstract
The 2',5'-oligoadenylate (2-5A) synthetase (OAS)-RNase L system is an IFN-induced antiviral pathway. RNase L activity depends on 2-5A, synthesized by OAS. Although all three enzymatically active OAS proteins in humans--OAS1, OAS2, and OAS3--synthesize 2-5A upon binding dsRNA, it is unclear which are responsible for RNase L activation during viral infection. We used clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (Cas9) technology to engineer human A549-derived cell lines in which each of the OAS genes or RNase L is knocked out. Upon transfection with poly(rI):poly(rC), a synthetic surrogate for viral dsRNA, or infection with each of four viruses from different groups (West Nile virus, Sindbis virus, influenza virus, or vaccinia virus), OAS1-KO and OAS2-KO cells synthesized amounts of 2-5A similar to those synthesized in parental wild-type cells, causing RNase L activation as assessed by rRNA degradation. In contrast, OAS3-KO cells synthesized minimal 2-5A, and rRNA remained intact, similar to infected RNase L-KO cells. All four viruses replicated to higher titers in OAS3-KO or RNase L-KO A549 cells than in parental, OAS1-KO, or OAS2-KO cells, demonstrating the antiviral effects of OAS3. OAS3 displayed a higher affinity for dsRNA in intact cells than either OAS1 or OAS2, consistent with its dominant role in RNase L activation. Finally, the requirement for OAS3 as the major OAS isoform responsible for RNase L activation was not restricted to A549 cells, because OAS3-KO cells derived from two other human cell lines also were deficient in RNase L activation.
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OAS2 and OAS3 belong to a family of pattern-recognition receptors involved in innate immune responses against both RNA and DNA viruses, with OAS3 considered essential in reducing viral titer during Chikungunya, Sindbis, influenza or vaccinia viral infections.
“These genes belong to a family of pattern-recognition receptors involved in innate immune responses against both RNA and DNA viruses, with OAS3 considered to be essential in reducing viral titer during Chikungunya, Sindbis, influenza or vaccinia viral infections [71].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [71]
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Double-Stranded RNA Sensors and Modulators in Innate Immunity
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“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.”
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Denisovan introgression has shaped the immune system of present-day Papuans
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“These genes belong to a family of pattern-recognition receptors involved in innate immune responses against both RNA and DNA viruses, with OAS3 considered to be essential in reducing viral titers during Chikungunya, Sindbis, influenza or vaccinia viral infections [49].”
- Authors
- Li, Y., Banerjee, S., Wang, Y., Goldstein, S. A., Dong, B., Gaughan, C., Silverman, R. H., & Weiss, S. R.
- Affiliations
- University of Pennsylvania (US)
- Cleveland Clinic (US)
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Weiss, Susan R.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-02-08
- Volume
- 113
- Issue
- 8
- Pages
- 2241-2246
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4776461
- OpenAlex
- W2263177460
- Cited by
- 285
- References
- 50
- Citations by year
- 2026: 42 · 2025: 28 · 2024: 34 · 2023: 19 · 2022: 32 · 2021: 33 · 2020: 24 · 2019: 37 · 2018: 19 · 2017: 13 · 2016: 3 · 2014: 1
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-06-10)
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01-AI104887)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01-NS081008)
- HHS | NIH | National Cancer Institute (R01-CA044059)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- RNase L activation, OAS3, 2',5'-oligoadenylate synthetase, double-stranded RNA, OAS1, OAS2, West Nile virus, Sindbis virus, influenza virus, vaccinia virus, rRNA degradation
- MeSH terms
- Cell Line, Endoribonucleases, Enzyme Activation, Humans, Influenza, Human, Models, Biological, RNA, Ribosomal, RNA, Viral, Sindbis Virus, Vaccinia, Virus Diseases, West Nile Fever, 2',5'-Oligoadenylate Synthetase, Alphavirus Infections, Gene Knockout Techniques, CRISPR-Cas Systems
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