A Highly Conserved Circular RNA circRasGEF1B Enhances Antiviral Immunity by Regulating miR-21-3p/MITA Pathway in Lower Vertebrates

Qing Chu; Weiwei Zheng; Hui Su; Lei Zhang; Renjie Chang; Wenya Gao; Tianjun Xu

doi:10.1128/JVI.02145-20

A Highly Conserved Circular RNA circRasGEF1B Enhances Antiviral Immunity by Regulating miR-21-3p/MITA Pathway in Lower Vertebrates

J Virol. 2021 Mar 10;95(7):e02145-20. doi: 10.1128/JVI.02145-20. Epub 2021 Jan 13.

Authors

Qing Chu^{1

2}, Weiwei Zheng^{1

2}, Hui Su¹, Lei Zhang¹, Renjie Chang¹, Wenya Gao¹, Tianjun Xu^{3

2

4

5}

Affiliations

¹ Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China.
² Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
³ Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China tianjunxu@163.com.
⁴ Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, China.
⁵ National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, China.

Abstract

Circular RNAs (circRNAs) represent a class of widespread, diverse, and covalently closed circRNAs that function as microRNA (miRNA) sponges and crucial regulators of gene expression in mammals. However, the regulation and function of circRNAs in lower vertebrates are still unknown. Here, we first discover a highly conserved circRNA termed circRasGEF1B, which displays a high conservation from mammals to fish and serves as key regulator in eliciting antiviral immunity in teleost fish. Results indicate that circRasGEF1B was highly expressed in Siniperca chuatsi rhabdovirus-infected tissues and cells. Functionally, miR-21-3p could inhibit cellular antiviral responses significantly, whereas circRasGEF1B counteract the effects of miR-21-3p. In mechanism, the results demonstrate that circRasGEF1B acts as a competing endogenous RNA (ceRNA) of miR-21-3p to relieve the repressive effect of miR-21-3p on its target MITA, then enhance the innate antiviral responses. Our results not only provide a novel insight into the functions of circRNAs in lower vertebrates, but broaden our understanding of circRNAs in viral infection.IMPORTANCE Siniperca chuatsi rhabdovirus (SCRV) is a typical fish RNA rhabdovirus, which is one of the most significant viral pathogens in teleost fish and can cause severe hemorrhagic septicemia in freshwater and marine fishes. Here, we discovered a highly conserved circRNAs called circRasGEF1B, which acts as a key regulator for innate antiviral responses upon SCRV infection. circRasGEF1B acts as an endogenous sponge of miR-21-3p that downregulates miR-21-3p expression levels. circRasGEF1B is able to bind to miR-21-3p directly and regulates MITA expression. To our knowledge, this report is the first to characterize circRNA-miRNA regulatory networks that exist in lower vertebrates.