Nuclear export of circular RNA

• 成果类型: Article
• 署名作者: Ngo, Linh H.; Bert, Andrew G.; Dredge, B. Kate; Williams, Tobias; Murphy, Vincent; Li, Wanqiu; Hamilton, William B.; Carey, Kirstyn T.; Toubia, John; Pillman, Katherine A.; Liu, Dawei; Desogus, Jessica; Chao, Jeffrey A.; Deans, Andrew J.; Goodall, Gregory J.; Wickramasinghe, Vihandha O.
• 署名单位: University of Melbourne; Peter Maccallum Cancer Center; University of Melbourne; Peter Maccallum Cancer Center; University of South Australia; Centre for Cancer Biology; SA Pathology; St. Vincent's Institute of Medical Research; Southern University of Science & Technology; Southern University of Science & Technology; University of Adelaide; Friedrich Miescher Institute for Biomedical Research; University of Basel; University of Adelaide; University of Melbourne; University of Adelaide; University of Adelaide; Friedrich Miescher Institute for Biomedical Research
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5846
• DOI: 10.1038/s41586-024-07060-5
• 发表日期: 2024-03-07
• 页码: 212-+
• 关键词: genome-wide analysis; messenger-rna; protein; sequence; precursor; complex; yeast; ran; transcription; activation

摘要

Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells(1-5), are formed by back-splicing of precursor mRNAs in the nucleus(6-10). 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.