https://orcid.org/0000-0003-4691-2518
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ABSTRACT
The innate immune system is the frontline host protection against pathogens. Effective antiviral immunity is elicited upon recognition of viral RNAs by the host pattern recognition receptors. One of the major viral RNA sensors is retinoic acid inducible gene-1, which triggers the production of interferons (IFNs). In turn, this protective response requires another viral sensor and immunity factor interferon-inducible protein kinase RNA activator (PACT/PRKRA). Here, we report the identification and characterization of a novel antisense PACT gene that expresses a non-coding RNA in a convergent and interferon-inducible manner. Publicly available gene structure and expression data revealed that this gene, that we termed ASPACT, overlaps with the 3′ -end of the PACT locus and is highly expressed during viral infection. Our results confirm the IFN-β-inducibility of ASPACT, which is dependent on STAT-1/2. We further discovered that downregulation of ASPACT impacts both the expression and localization of the PACT transcript. At the transcription level, ChIP and ChIRP assays demonstrated that the ASPACT non-coding RNA occupies distinct chromatin regions of PACT gene and is important for promoter recruitment of the epigenetic silencer HDAC1. In parallel, ASPACT was also found to mediate nuclear retention of the PACT mRNA via direct RNA–RNA interaction, as revealed by RNA antisense purification assay. In summary, our results support the model that the non-coding RNA ASPACT acts as a negative regulator of PACT at multiple levels, and reveal a novel regulator of the viral counteractive response.
Acknowledgments
We are grateful to members of the BC-MT laboratory for critical reading of the article and important discussions. This work was supported by grants from the Ministry of Science and Technology of Taiwan (MOST106–2320-B-182–035-MY3 to HL; MOST105-2314-B-182-061-MY4 and MOST107-2320-B-182-042-MY3 to BC-MT), Chang Gung Memorial Hospital (CMRPD1F0573, CMRPD1H0371, and BMRPF45 to HL; CMRPD1F0443, CMRPD1H0022, CMRPD1H0261, and BMRP960 to BC-MT), and the Ministry of Education of Taiwan. This work was also financially supported by the Research Center for Emerging Viral Infections from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and the Ministry of Science and Technology (MOST), Taiwan (MOST108-3017-F-182-001).
Disclosure statement
No potential conflict of interest was reported by the authors.
Supplementary material
Supplemental data for this article can be accessed here
