Abstract
Vault particles are conserved organelles implicated in multidrug resistance and intracellular transport. They contain three different proteins and non-coding vault RNAs (vRNAs). Here we show that human vRNAs produce several small RNAs (svRNAs) by mechanisms different from those in the canonical microRNA (miRNA) pathway. At least one of these svRNAs, svRNAb, associates with Argonaute proteins to guide sequence-specific cleavage and regulate gene expression similarly to miRNAs. We demonstrate that svRNAb downregulates CYP3A4, a key enzyme in drug metabolism. Our findings expand the repertoire of small regulatory RNAs and assign, for the first time, a function to vRNAs that may help explain the association between vault particles and drug resistance.
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Acknowledgements
This work was supported by grants from The Royal Physiographic Society in Lund, the Berta Kamprad Foundation, the Lund Center for Stem Cell Biology and Cell Therapy, and the Swedish Cancer Society. We thank M. Siomi and H. Siomi for the gift of the Ago antibodies, and A. Brun and C. Welinder for technical advice. HP was supported by the Swedish Knowledge Foundation through the Industrial PhD program in Medical Bioinformatics at the Strategy and Development Office at the Karolinska Institute.
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H.P. carried out experimental work and participated in the design of the study. H.P. and A.K. performed the bioinformatic analyses. J.V.C. analysed the microarray data. P.M. contributed to the bioinformatic analyses. Å.B. participated in the design of the study. C.R. contributed to the experimental work, and conceived, designed and coordinated the study. H.P., A.K. and C.R. wrote the manuscript.
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Persson, H., Kvist, A., Vallon-Christersson, J. et al. The non-coding RNA of the multidrug resistance-linked vault particle encodes multiple regulatory small RNAs. Nat Cell Biol 11, 1268–1271 (2009). https://doi.org/10.1038/ncb1972
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DOI: https://doi.org/10.1038/ncb1972
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