The circular RNA circATP8B(2) regulates ROS production and antiviral immunity in Drosophila
Weihong Liang,
Wei Liu,
Xiao-Peng Xiong,
Jennifer W. Li,
Jian-Liang Li,
Ranjan J. Perera,
Rui Zhou
Affiliations
Weihong Liang
Departments of Medicine, Biological Chemistry, & Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins All Children’s Hospital, St. Petersburg, FL 33701, USA
Wei Liu
Departments of Medicine, Biological Chemistry, & Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins All Children’s Hospital, St. Petersburg, FL 33701, USA
Xiao-Peng Xiong
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Jennifer W. Li
Department of Medicine, Brown University, Providence, RI 02912, USA
Jian-Liang Li
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; National Institute of Environmental Health Sciences, Durham, NC 27709, USA
Ranjan J. Perera
Departments of Medicine, Biological Chemistry, & Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins All Children’s Hospital, St. Petersburg, FL 33701, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Rui Zhou
Departments of Medicine, Biological Chemistry, & Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins All Children’s Hospital, St. Petersburg, FL 33701, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: We identified and validated a collection of circular RNAs (circRNAs) in Drosophila melanogaster. We show that depletion of the pro-viral circRNA circATP8B(2), but not its linear siblings, compromises viral infection both in cultured Drosophila cells and in vivo. In addition, circATP8B(2) is enriched in the fly gut, and gut-specific depletion of circATP8B(2) attenuates viral replication in an oral infection model. Furthermore, circATP8B(2) depletion results in increased levels of reactive oxygen species (ROS) and enhanced expression of dual oxidase (Duox), which produces ROS. Genetic and pharmacological manipulations of circATP8B(2)-depleted flies that reduce ROS levels rescue the viral replication defects elicited by circATP8B(2) depletion. Mechanistically, circATP8B(2) associates with Duox, and circATP8B(2)-Duox interaction is crucial for circATP8B(2)-mediated modulation of Duox activity. In addition, Gαq, a G protein subunit required for optimal Duox activity, acts downstream of circATP8B(2). We conclude that circATP8B(2) regulates antiviral defense by modulating Duox expression and Duox-dependent ROS production.
