Nuclear export of circular RNA

Linh H. Ngo, Andrew G. Bert, B. Kate Dredge, Tobias Williams, Vincent Murphy, Wanqiu Li, William B. Hamilton, Kirstyn T. Carey, John Toubia, Katherine A. Pillman, Dawei Liu, Jessica Desogus, Jeffrey A. Chao, Andrew J. Deans, Gregory J. Goodall () and Vihandha O. Wickramasinghe ()
Additional contact information
Linh H. Ngo: University of Melbourne
Andrew G. Bert: University of South Australia and SA Pathology
B. Kate Dredge: University of South Australia and SA Pathology
Tobias Williams: University of Melbourne
Vincent Murphy: St Vincent’s Institute of Medical Research
Wanqiu Li: University of Melbourne
William B. Hamilton: University of Melbourne
Kirstyn T. Carey: University of Melbourne
John Toubia: University of South Australia and SA Pathology
Katherine A. Pillman: University of South Australia and SA Pathology
Dawei Liu: University of South Australia and SA Pathology
Jessica Desogus: Friedrich Miescher Institute for Biomedical Research
Jeffrey A. Chao: Friedrich Miescher Institute for Biomedical Research
Andrew J. Deans: St Vincent’s Institute of Medical Research
Gregory J. Goodall: University of South Australia and SA Pathology
Vihandha O. Wickramasinghe: University of Melbourne

Nature, 2024, vol. 627, issue 8002, 212-220

Abstract: Abstract Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells1–5, are formed by back-splicing of precursor mRNAs in the nucleus6–10. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here we identify a pathway that is specific for the nuclear export of circular RNA. This pathway requires Ran-GTP, exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter CRM1 selectively increases the nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA-binding proteins reveals that interaction between IGF2BP1 and circRNA is enhanced by Ran-GTP. The formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with exportin-2, circRNA and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and exportin-2 to export circRNAs in a mechanism that is analogous to protein export, rather than mRNA export.

Date: 2024
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DOI: 10.1038/s41586-024-07060-5

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