XPO5 is required for miRNA biogenesis and promotes primary miRNA processing independent of RanGTP

XPO5 mediates nuclear export of miRNA hairpin precursors in a RanGTP-dependent manner. However, the requirement of XPO5 for global miRNA biogenesis and mammalian development and XPO5-associated RNA species are not determined. Here we show that XPO5 is required for mouse embryonic development and morphogenesis of skin and brain. Loss of XPO5 compromises the biogenesis of most miRNAs and that leads to severe developmental defects. Surprisingly, XPO5 not only associates with miRNA hairpin precursors but also pervasively binds to double-stranded RNA (dsRNA) regions found in many cellular RNAs and some clustered pri-miRNAs. The binding of XPO5 to miR-17~92 pri-miRNAs is RanGTP-independent. Pre-incubation with XPO5 enhances the processing efficiency of the DROSHA/DGCR8 microprocessor. Together, our studies demonstrate the requirement of XPO5 for miRNA biogenesis and mouse development, reveal an unexpected role of XPO5 for recognizing and facilitating the nuclear cleavage of clustered pri-miRNAs and identify numerous cellular RNAs as novel XPO5 subtracts. Examination of RNA substrates of XPO5 in HEK293FT cells

XPO5以依赖RanGTP的方式介导微小RNA（miRNA）发夹前体的核输出。然而，XPO5对于全局miRNA生物发生、哺乳动物发育的必要性，以及与XPO5结合的RNA物种仍未明确。本研究表明，XPO5对小鼠胚胎发育以及皮肤和大脑的形态发生至关重要。XPO5的缺失会损害大多数miRNA的生物发生过程，进而引发严重的发育缺陷。令人意外的是，XPO5不仅可结合miRNA发夹前体，还能广泛结合众多细胞RNA及部分成簇初级微小RNA（pri-miRNA）中的双链RNA（double-stranded RNA, dsRNA）区域。XPO5与miR-17~92 pri-miRNA的结合不依赖RanGTP。预先与XPO5共孵育可提升DROSHA/DGCR8微处理器复合物的加工效率。综上，本研究证实了XPO5对于miRNA生物发生及小鼠发育的必要性，揭示了XPO5识别并促进成簇pri-miRNA核切割的全新功能，并将众多细胞RNA鉴定为新型XPO5底物。本研究对HEK293FT细胞内XPO5的RNA底物展开了检测。