A virus-induced circular RNA maintains latent infection of Kaposi’s sarcoma herpesvirus

Takanobu Tagawa, Daniel Oh, Sarah Dremel, Guruswamy Mahesh, Vishal N. Koparde, Gerard Duncan, Thorkell Andresson, Joseph M. Ziegelbauer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Non-coding RNAs (ncRNAs) play important roles in host-pathogen interactions; oncogenic viruses like Kaposi’s sarcoma herpesvirus (KSHV) employ ncRNAs to establish a latent reservoir and persist for the life of the host. We previously reported that KSHV infection alters a novel class of RNA, circular RNAs (circRNAs). CircRNAs are alternative splicing isoforms and regulate gene expression, but their importance in infection is largely unknown. Here, we showed that a human circRNA, hsa_circ_0001400, is induced by various pathogenic viruses, namely KSHV, Epstein-Barr virus, and human cytomegalovirus. The induction of circRNAs including circ_0001400 by KSHV is co-transcriptionally regulated, likely at splicing. Consistently, screening for circ_0001400-interactingproteins identified a splicing factor, PNISR. Functional studies using infected primary endothelial cells revealed that circ_0001400 inhibits KSHV lytic transcription and virus production. Simultaneously, the circRNA promoted cell cycle, inhibited apoptosis, and induced immune genes. RNA-pull down assays identified transcripts interacting withcirc_0001400, including TTI1, which is a component of the pro-growth mTOR complexes. We thus identified a circRNA that is pro-growth and anti-lytic replication. These results support a model in which KSHV induces circ_0001400 expression to maintain latency. Since circ_0001400 is induced by multiple viruses, this novel viral strategy maybe widely employed by other viruses.
Original languageEnglish
Article numbere2212864120
Number of pages11
JournalProceedings of the National Academy of Sciences
Volume120
Issue number6
Early online date1 Feb 2023
DOIs
Publication statusPublished - 7 Feb 2023
Externally publishedYes

Keywords / Materials (for Non-textual outputs)

  • KSHV
  • HHV8
  • circular RNAs
  • herpesvirus

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