OAS1 and OAS3 negatively regulate the expression of chemokines and interferon-responsive genes in human macrophages

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. 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.

The role of ZAP and OAS3/RNAseL pathways in the attenuation of an RNA virus with elevated frequencies of CpG and UpA dinucleotides

“…However, preliminary evidence for the existence of a cross-regulatory interaction between ZAP and RNAseL/OAS3 might include the observation that ZAP k/o leads to much greater constitutive expression of RNAseL (Figure 13B). Conversely, OAS3 k/o leads to an upregulation of ISG expression activated through MAVS (67). However, further work is needed to disentangle direct effects between these antiviral pathways and effects mediated through differences in interferon induction and secondary activation of ZAP, OASs and RNAseL expression.…”

Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma

“…19,20 OAS3 can synthesize 2 0 , 5 0 -oligoadenylates (2-5A) from ATP on binding to double-stranded (ds)RNA and is specialized for binding long dsRNA. 21 OAS3 activates RNase L endonuclease in response to FIGURE 3. Location and conservation of mutated amino acid residue, and the expression of OAS3.…”

“…exogenous RNA from either virus or bacteria, [21][22][23][24] suggesting that the OAS/RNaseL pathway is a major antiviral defense mechanism. [21][22][23][24][25] Recent research revealed that OAS3 could activate RNase L and inhibited ZIKA virus replication. 26 Therefore, OAS3 mutation enhances the host's susceptibility to viral or bacterial infection, which in turn, activates their inflammation.…”

Bioinformatics analysis of Ewing's sarcoma: Seeking key candidate genes and pathways

“…The 2′-5′-oligoadenylate synthetase 1 (OAS1) belongs to the OAS family, which inhibits cellular protein synthesis and resistance to viral infection (35). Lee et al (36) demonstrated that OAS1 negatively regulates the expression of chemokines and interferon-responsive genes in human macrophages. Literature search results did not reveal any association between OAS and the carcinogenesis or progression of tumors; thus suggesting that ES occurrence may be associated with OAS1, but further investigations are required.…”