Despite intensive studies, the molecular mechanisms by which the genetic materials are uploaded into microvesicles (MVs) are still unknown. This is the first study describing a zipcode-like 25 nucleotide (nt) sequence in the 3'-untranslated region (3'UTR) of mRNAs, with variants of this sequence present in many mRNAs enriched in MVs, as compared to their glioblastoma cells of origin. When this sequence was incorporated into the 3'UTR of a reporter message and expressed in a different cell type, it led to enrichment of the reporter mRNA in MVs. Critical features of this sequence are both a CUGCC core presented on a stemloop structure and a miRNA-binding site, with increased levels of the corresponding miRNA in cells further increasing levels of mRNAs in MVs.
Bibliographical noteFunding Information:
We thank Ms Suzanne McDavitt for skilled editorial assistance, Leonora Balaj for help with RNA work, and Johan Skog for the microarray data presented in Supplementary Table S1 . Support for this work was provided by NIH NCI grant CA141150 (X.O.B.), NIH NINDS grant NS037409 (X.O.B. and O.S.), and Forschungsgesellschaft for Brain Tumors (O.S.). The authors declared no competing financial interests.