4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay

Current models of mRNA turnover indicate that cytoplasmic degradation is coupled with translation. However, our understanding of the molecular events that coordinate ribosome transit with the mRNA decay machinery is still limited. Here, we show that the 4EHP–GIGYF1/2 complexes trigger co-translational mRNA decay as a result of perturbed elongation. Human cells lacking 4EHP and GIGYF1/2 proteins accumulate transcripts known to be degraded in a translation-dependent manner or with prominent ribosome pausing. These include among others, mRNAs encoding secretory and membrane-bound proteins or α- and β-tubulin subunits. In addition, 4EHP–GIGYF1/2 complexes fail to reduce target mRNA levels in the absence of ribosome stalling or upon disruption of their interaction with the mRNA cap structure, DDX6 or GYF domain-associated factors. Our studies reveal how a repressor complex linked to neurological disorders minimizes the protein output of a subset of mRNAs.