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

More than 2,700 human mRNA 3′UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs encode proteins strongly enriched for long intrinsically disordered regions (IDRs) with hydrophobic amino acid clusters. For MYC, UTX, and JMJD3, we show that their mRNA 3′UTRs control protein activity. Rather than affecting protein abundance or localization, we find that the KDM6B 3′UTR co-translationally changes the folding of JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA has IDR chaperone activity that prevents interference of hydrophobic clusters in the IDR with folding of the structured domain. 3′UTRs with chaperone activity are multivalent and meshlike condensate-enriched, indicating the presence of localized folding environments for IDR-containing proteins. We show here that the protein sequence is insufficient for cellular biogenesis of fully active IDR-containing transcriptional regulators, suggesting that mRNA 3′UTRs control their activity by preventing co-translational misfolding.