Argonaute proteins function in small interfering RNA (siRNA)-mediated cytoplasmic RNA interference (RNAi). But Guang et al. now describe a function for the Caenorhabditis elegans Argonaute protein NRDE-3 in the nuclear import of siRNAs and in nuclear RNAi.
A genetic screen identified mutations in nrde-3 that resulted in animals that were defective in nuclear RNAi; however, cytoplasmic RNAi was unaffected in nrde-3-mutant worms. The mutant phenotype could be rescued by a fusion protein of wild-type NRDE-3 with green fluorescent protein. Whereas wild-type NRDE-3 localized to the nucleus, mutation of the siRNA-binding PAZ domain of NRDE-3 caused the redistribution of the protein to the cytoplasm. Animals that were defective for endogenous (endo)-siRNA production also had cytoplasmic NRDE-3, which indicates that binding of endo-siRNA to NRDE-3 is essential for its nuclear localization.
...NRDE-3 is responsible for silencing nuclear-localized RNAs...
The authors also showed that NRDE-3 is responsible for silencing nuclear-localized RNAs, including pre-mRNAs, although the mechanisms of nuclear silencing remain unknown. The absence of the conserved catalytic residues that are essential for endonuclease activity further supports the notion that NRDE-3 is likely to be unimportant for cytoplasmic RNAi. In addition, the 5′ ends of endo-siRNAs in association with NRDE-3 suggest that these siRNAs have been generated by RNA-dependent RNA polymerases. This implies that NRDE-3-mediated nuclear RNAi is probably a downstream function of primary RNAi events in the cytoplasm.
So, is nuclear silencing dependent on the nuclear localization of NRDE-3? Mutant NRDE-3 that lacked its nuclear localization signal failed to rescue the nrde-3-mutant phenotype. Therefore, NRDE-3 must localize to the nucleus to trigger nuclear RNAi. It is possible that NRDE-3 is required only for nuclear import and that a second Argonaute protein mediates nuclear RNAi. It would also be interesting to test whether other types of small RNAs that are known to function in the nucleus, such as Piwi-interacting RNAs, are imported into the nucleus by similar mechanisms.
References
ORIGINAL RESEARCH PAPER
Guang, S. et al. An Argonaute transports siRNAs from the cytoplasm to the nucleus. Science 321, 537–541 (2008)
FURTHER READING
Hutvagner, G. & Simard, M. J. Argonaute proteins: key players in RNA silencing. Nature Rev. Mol. Cell Biol. 9, 22–32 (2008)
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Heinrichs, A. Argonaute on the move. Nat Rev Mol Cell Biol 9, 666 (2008). https://doi.org/10.1038/nrm2473
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DOI: https://doi.org/10.1038/nrm2473