Translational Control via Protein-Regulated Upstream Open Reading Frames

Analysis of the regulation of msl-2 mRNA by Sex lethal (SXL), which is critical for dosage compensation in Drosophila, has uncovered a mode of translational control based on common 5′ untranslated region elements, upstream open reading frames (uORFs), and interaction sites for RNA-binding proteins. We show that SXL binding downstream of a short uORF imposes a strong negative effect on major reading frame translation. The underlying mechanism involves increasing initiation of scanning ribosomes at the uORF and augmenting its impediment to downstream translation. Our analyses reveal that SXL exerts its effect controlling initiation, not elongation or termination, at the uORF. Probing the generality of the underlying mechanism, we show that the regulatory module that we define experimentally functions in a heterologous context, and we identify natural Drosophila mRNAs that are regulated via this module. We propose that protein-regulated uORFs constitute a systematic principle for the regulation of protein synthesis. [Display omitted] ► Drosophila SXL protein cooperates with a uORF to regulate msl-2 mRNA translation ► SXL-mediated regulation targets translation initiation, not elongation or termination ► SXL promotes ribosome recognition of a uORF, thereby inhibiting msl-2 translation ► Protein-regulated uORFs may define a general mechanism for the control of translation