Upon viral infection, the 2', 5'-oligoadenylate synthetase (OAS)-ribonuclease L (RNaseL) system works to cleave viral RNA, thereby blocking viral replication. However, it is unclear whether OAS proteins have a role in regulating gene expression. Here, we show that OAS1 and OAS3 act as negative regulators of the expression of chemokines and interferonresponsive genes in human macrophages. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (Cas9) technology was used to engineer human myeloid cell lines in which the OAS1 or OAS3 gene was deleted. Neither OAS1 nor OAS3 was exclusively responsible for the degradation of rRNA in macrophages stimulated with poly(I:C), a synthetic surrogate for viral double-stranded (ds)RNA. An mRNA sequencing analysis revealed that genes related to type I interferon signaling and chemokine activity were increased in OAS1 -/- and OAS3 -/- macrophages treated with intracellular poly(I:C). Indeed, retinoic-acid-inducible gene (RIG)-I- and interferon-induced helicase C domain-containing protein (IFIH1 or MDA5)-mediated induction of chemokines and interferon-stimulated genes was regulated by OAS3, but Toll-like receptor 3 (TLR3)- and TLR4-mediated induction of those genes was modulated by OAS1 in macrophages. However, stimulation of these cells with type I interferons had no effect on OAS1- or OAS3- mediated chemokine secretion. These data suggest that OAS1 and OAS3 negatively regulate the expression of chemokines and interferon-responsive genes in human macrophages.
Bibliographical noteFunding Information:
This research was supported by the Basic Science Research Program of the NRF, funded by the Ministry of Science, ICT & Future Planning (NRF-2017R1D1A1B06029547 to J.S.K-H), by the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation of Korea (NRF), which is funded by the Ministry of Science, Communications Technology (ICT), and Future Planning (grant number: 2016M3C9A4921712, to Y.J.K.), and by an intramural grant (2Z05610, to W.-B.L.) from the Korea Institute of Science and Technology (KIST), Republic of Korea.
© 2019 by the The Korean Society for Biochemistry and Molecular Biology.
All Science Journal Classification (ASJC) codes
- Molecular Biology