mRNA 3′UTRs chaperone intrinsically disordered regions to control protein activity

Nearly 3,000 human mRNA 3′UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. We show that these proteins are only fully active when translated from mRNA templates that include their 3′UTRs, raising the possibility of functional interactions between 3′UTRs and IDRs. Rather than affecting protein abundance or localization, we find that the KDM6B 3′UTR in the mRNA template changes the folding of the encoded IDR-containing JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA acts as IDR chaperone that prevents interference of hydrophobic clusters in the IDR with folding of the structured domain. mRNA-based IDR chaperones are enriched in meshlike cytoplasmic condensates, suggesting localized chaperone activity. As hydrophobic clusters in IDRs are widespread, our data suggest that 3′UTR-dependent protein folding could be a widely used mechanism for activity regulation of transcriptional regulators.