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

Cell Rep. 2020 Oct 13;33(2):108262. 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.

Keywords: DDX6; GYF domain; endoplasmic reticulum; mRNA decay; nascent chain; ribosome pausing; signal peptide; translation; tubulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Eukaryotic Initiation Factor-4E / metabolism*
  • HEK293 Cells
  • Humans
  • Membrane Proteins / metabolism
  • Protein Binding
  • Protein Biosynthesis*
  • Protein Domains
  • RNA Stability*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Ribosomes / metabolism
  • Tubulin / metabolism


  • Carrier Proteins
  • EIF4E2 protein, human
  • Eukaryotic Initiation Factor-4E
  • GIGYF1 protein, human
  • GIGYF2 protein, human
  • Membrane Proteins
  • RNA, Messenger
  • Tubulin
  • ZNF598 protein, human