A nuclear import pathway exploited by pathogenic noncoding RNAs

Abstract

The prevailing view of intracellular RNA trafficking in eukaryotic cells is that RNAs transcribed in the nucleus either stay in the nucleus or cross the nuclear envelope, entering the cytoplasm for function. However, emerging evidence illustrates that numerous functional RNAs move in the reverse direction, from the cytoplasm to the nucleus. The mechanism underlying RNA nuclear import has not been well elucidated. Viroids are single-stranded circular noncoding RNAs that infect plants. Using Nicotiana benthamiana, tomato (Solanum lycopersicum), and nuclear-replicating viroids as a model, we showed that cellular IMPORTIN ALPHA-4 (IMPa-4) is likely involved in viroid RNA nuclear import, empirically supporting the involvement of Importin-based cellular pathway in RNA nuclear import. We also confirmed the involvement of a cellular protein (VIRP1) that binds both IMPa-4 and viroids. Moreover, a conserved C-loop in nuclear-replicating viroids serves as a key signal for nuclear import. Disrupting C-loop impairs VIRP1 binding, viroid nuclear accumulation and infectivity. Further, C-loop exists in a subviral satellite noncoding RNA that relies on VIRP1 for nuclear import. These results advance our understanding of subviral RNA infection and the regulation of RNA nuclear import.

RNA three-dimensional structure drives the sequence organization of potato spindle tuber viroid quasispecies

“…Previous studies have revealed that S26 is a component of the RY motif, which serves as the binding site for the viroid RNA binding protein (Virp1) [ 49 ]. This protein interacts with IMPORTIN ALPHA-4 to facilitate the nuclear import of PSTVd [ 50 ]. While the role of this stem in the cell-to-cell movement and systemic trafficking of PSTVd remains unclear, our data also suggests its potential involvement in these two processes.…”

Viroids, Satellite RNAs and Prions: Folding of Nucleic Acids and Misfolding of Proteins

“…Viroids are now subdivided into the families Pospiviroidae and Avsunviroidae , which are located mainly in the nucleus and the chloroplast, respectively. Their locations also suggest their usage of different replication strategies, host polymerases, structural elements, and trafficking [ 13 , 109 , 110 , 111 ]. The knowledge on viroid-induced symptoms is increasing, but still not solved fully.…”

“… Timeline of research development of viroids (green text) [ 4 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], satellite RNAs (orange text) [ 11 , 12 , 45 , 46 , 47 , 48 , 49 ], prions (red text) [ 7 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , …”

CircAMOTL1 RNA and AMOTL1 Protein: Complex Functions of AMOTL1 Gene Products

“…The exact mechanism leading to the nuclear translocation of circAMOTL1 in wound healing or cardiac repair is also unknown. Interestingly, in viroids-infecting plants, nuclear import is driven by forming a C-loop on the circular RNA, which is recognized by VIRP1 that serves as a scaffold for Importin alpha-4 to mediate nuclear transport [112]. Similar mechanisms involving the formation of particular secondary structures and interactions with adaptor proteins could regulate the intracellular transport of circRNAs.…”