GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control

Mol Cell. 2020 Sep 17;79(6):950-962.e6. doi: 10.1016/j.molcel.2020.07.007. Epub 2020 Jul 28.


Ribosome-associated quality control (RQC) pathways protect cells from toxicity caused by incomplete protein products resulting from translation of damaged or problematic mRNAs. Extensive work in yeast has identified highly conserved mechanisms that lead to degradation of faulty mRNA and partially synthesized polypeptides. Here we used CRISPR-Cas9-based screening to search for additional RQC strategies in mammals. We found that failed translation leads to specific inhibition of translation initiation on that message. This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP. Model substrates and growth-based assays established that inhibition of additional rounds of translation acts in concert with known RQC pathways to prevent buildup of toxic proteins. Inability to block translation of faulty mRNAs and subsequent accumulation of partially synthesized polypeptides could explain the neurodevelopmental and neuropsychiatric disorders observed in mice and humans with compromised GIGYF2 function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems / genetics
  • Carrier Proteins / genetics*
  • Eukaryotic Initiation Factor-4E / genetics*
  • Humans
  • Mice
  • Peptide Chain Initiation, Translational*
  • Protein Biosynthesis / genetics
  • Protein Processing, Post-Translational / genetics
  • Quality Control
  • RNA, Messenger / genetics
  • Ribosomes / genetics*
  • Ubiquitin-Protein Ligases / genetics


  • Carrier Proteins
  • EIF4E2 protein, human
  • Eukaryotic Initiation Factor-4E
  • GIGYF2 protein, human
  • RNA, Messenger
  • Ubiquitin-Protein Ligases