Hsa_circ_0007321 regulates Zika virus replication through miR-492/NFKBID/NF-κB signaling pathway

Abstract

ABSTRACT Circular RNAs (CircRNAs) have been shown to play a critical role in regulating viral infection and replication. We performed RNA sequencing to identify differentially expressed circRNAs in A549 human lung adenocarcinoma cells with and without Zika virus (ZIKV) infection. Notably, hsa_circ_0007321 was significantly downregulated after ZIKV infection. We then explored the role and mechanism of hsa_circ_0007321 in the regulation of ZIKV replication. Hsa_circ_0007321, derived from exons 2, 3, 4, and 5 of the DIS3L2 (DIS3 like 3'−5' exoribonuclease 2) gene, was mainly enriched in cytoplasm. We found that the knockdown of hsa_circ_0007321 significantly increased microRNA-492 levels to decrease NFKBID (NFKB inhibitor delta) expression, leading to the activation of the nuclear factor-κB (NF-κB) signaling pathway, inflammatory cytokine production, and subsequently, inhibition of ZIKV replication. These findings illustrate that hsa_circ_0007321 acts as a competitive endogenous RNA that regulates ZIKV replication through the miR-492/NFKBID NF-κB signaling pathway. IMPORTANCE Over the past decade, increasing evidence has shown that circular RNAs (circRNAs) play important regulatory roles in viral infection and host antiviral responses. However, reports on the role of circRNAs in Zika virus (ZIKV) infection are limited. In this study, we identified 45 differentially expressed circRNAs in ZIKV-infected A549 cells by RNA sequencing. We clarified that a downregulated circRNA, hsa_circ_0007321, regulates ZIKV replication through targeting of miR-492 and the downstream gene NFKBID. NFKBID is a negative regulator of nuclear factor-κB (NF-κB), and we found that inhibition of the NF-κB pathway promotes ZIKV replication. Therefore, this finding that hsa_circ_0007321 exerts its regulatory role on ZIKV replication through the miR-492/NFKBID/NF-κB signaling pathway has implications for the development of strategies to suppress ZIKV and possibly other viral infections.