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OAS1 and OAS3 negatively regulate the expression of chemokines and interferon-responsive genes in human macrophages
Wook-Bin Lee1, Won Young Choi2, Dong-Hyun Lee2, Hyeran Shim3,4, Jeongsil Kim-Ha3, Young-Joon Kim2,4,*
1Natural Products Research, Korea Institute of Science and Technology (KIST) Gangneung Institute of Natural Products,
2Department of Integrated Omics for Biomedical Science, Yonsei University,
3Department of Integrative Bioscience and Biotechnology, Sejong University,
4Department of Biochemistry, Yonsei University
Abstract
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 interferon-responsive 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. A 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.
Abstract, Accepted Manuscript(in press) [Submitted on June 15, 2018, Accepted on July 9, 2018]
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