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

Kelsey L. Hickey, Kimberley Dickson, J. Zachery Cogan, Joseph M. Replogle, Michael Schoof, Karole N. D'Orazio, Niladri K. Sinha, Jeffrey A. Hussmann, Marco Jost, Adam Frost, Rachel Green, Jonathan S. Weissman, Kamena K. Kostova

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)950-962.e6
JournalMolecular cell
Volume79
Issue number6
DOIs
StatePublished - Sep 17 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hickey, K. L., Dickson, K., Cogan, J. Z., Replogle, J. M., Schoof, M., D'Orazio, K. N., Sinha, N. K., Hussmann, J. A., Jost, M., Frost, A., Green, R., Weissman, J. S., & Kostova, K. K. (2020). GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control. Molecular cell, 79(6), 950-962.e6. https://doi.org/10.1016/j.molcel.2020.07.007