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

• Published in: Cell reports (Cambridge) 2020-10, Vol.33 (2), p.108262-108262, Article 108262
• Main Authors: Weber, Ramona, Chung, Min-Yi, Keskeny, Csilla, Zinnall, Ulrike, Landthaler, Markus, Valkov, Eugene, Izaurralde, Elisa, Igreja, Cátia
• Format: Article
• Language: English
• Subjects: Carrier Proteins - chemistry; Carrier Proteins - metabolism; DDX6; endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Eukaryotic Initiation Factor-4E - metabolism; GYF domain; HEK293 Cells; Humans; Membrane Proteins - metabolism; mRNA decay; nascent chain; Protein Binding; Protein Biosynthesis; Protein Domains; ribosome pausing; Ribosomes - metabolism; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; signal peptide; translation; tubulin; Tubulin - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108262

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 4EHP-GIGYF1/2 complexes trigger co-translational mRNA decay. Human cells lacking these proteins accumulate mRNAs with prominent ribosome pausing. They include, among others, transcripts encoding secretory and membrane-bound proteins or tubulin subunits. In addition, 4EHP-GIGYF1/2 complexes fail to reduce mRNA levels in the absence of ribosome stalling or upon disruption of their interaction with the cap structure, DDX6, and ZNF598. We further find that co-translational binding of GIGYF1/2 to the mRNA marks transcripts with perturbed elongation to decay. Our studies reveal how a repressor complex linked to neurological disorders minimizes the protein output of a subset of mRNAs. [Display omitted] •4EHP and GIGYF1/2 induce co-translational mRNA decay•Targeted transcripts are characterized by ribosome pausing and collision•mRNA decay requires ribosome pausing, DDX6, and partially ZNF598•Identified mRNAs encode secreted and membrane-bound proteins or tubulin subunits The quality of the proteome is crucial for cell survival. Weber et al. show that the destruction of a subset of messages marked by altered ribosome activity is triggered by the 4EHP-GIGYF1/2 complexes during protein synthesis. This function of the complexes averts the production of unwanted or cytotoxic proteins.