A previously unidentified circRNA inhibits virus replication by regulating the miR-24-3p/KEAP1 axis

PLoS Pathog. 2024 Dec 17;20(12):e1012712. doi: 10.1371/journal.ppat.1012712. eCollection 2024 Dec.

Abstract

Circular RNAs (circRNAs) exert diverse biological functions in different processes. However, the role of circRNAs during virus infection is mostly unknown. Herein, we explored the characteristics of host circRNAs using alphaherpesvirus pseudorabies virus (PRV) as a model. PRV infection upregulated the expression of circRNA circ29164, which does not encode a protein. RNA pulldown assays identified that circ29164 interacts with the microRNA ssc-miRNA-24-3p. Further analysis indicated that ssc-miR-24-3p targets the mRNA encoding kelch-like ECH-associated protein 1 (KEAP1), and circ29164 competitively binds to ssc-miR-24-3p to prevent it binding to Keap1. Apoptosis detection demonstrated that circ29164 or Keap1 overexpression, but not knockdown, induced caspase 3 activity and the release of cytochrome C from mitochondria, and inhibited PRV replication. Taken together, these data identified a previously undiscovered circRNA, circ29164, which inhibits PRV replication by competitively binding to ssc-24-3p to maintain KEAP1 levels.

MeSH terms

  • Animals
  • Apoptosis
  • Herpesvirus 1, Suid* / genetics
  • Humans
  • Kelch-Like ECH-Associated Protein 1* / genetics
  • Kelch-Like ECH-Associated Protein 1* / metabolism
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Pseudorabies / genetics
  • Pseudorabies / metabolism
  • Pseudorabies / virology
  • RNA, Circular* / genetics
  • RNA, Circular* / metabolism
  • Virus Replication*

Substances

  • Kelch-Like ECH-Associated Protein 1
  • RNA, Circular
  • MicroRNAs
  • KEAP1 protein, human

Grants and funding

This study was supported by the National Natural Foundation of China (Grant No. 32192454) to JYZ, the National Key Research and Development Programs of China (Grant No. 2021YFD1801102) to JYZ, the Fundamental Research Funds for the Central Universities (Grant No. 2022-KYY-517101-0005) to JYZ and Hangzhou Chengxi Sci-tech innovation Corridor Management Committee to JYZ. The funders had no role in study design, date collection and analysis, decision to publish, or preparation of the manuscript.