Elongation stall directs gene-specific translation in the integrated stress response

Sara K. Young, Lakshmi Reddy Palam, Cheng Wu, Matthew S. Sachs, Ronald Wek

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Upon exposure to environmental stress, phosphorylation of theα subunit of eIF2 (eIF2α-P) represses global protein synthesis, coincident with preferential translation of gene transcripts that mitigate stress damage or alternatively trigger apoptosis. Because there are multiple mammalian eIF2 kinases, each responding to different stress arrangements, this translational control scheme is referred to as the integrated stress response (ISR). Included among the preferentially translated mRNAs induced by eIF2α-P is that encoding the transcription factor CHOP (DDIT3/GADD153). Enhanced levels of CHOP promote cell death when ISR signaling is insufficient to restore cell homeostasis. Preferential translation of CHOP mRNA occurs by a mechanism involving ribosome bypass of an inhibitory upstream ORF (uORF) situated in the 5'-leader of the CHOP mRNA. In this study, we used biochemical and genetic approaches to define the inhibitory features of the CHOP uORF and the biological consequences of loss of the CHOP uORF on CHOP expression during stress. We discovered that specific sequences within theCHOPuORF serve to stall elongating ribosomes and prevent ribosome reinitiation at the downstream CHOP coding sequence. As a consequence, deletion of the CHOP uORF substantially increases the levels and modifies the pattern of induction of CHOP expression in the ISR. Enhanced CHOP expression leads to increased expression of key CHOP target genes, culminating in increased cell death in response to stress.

Original languageEnglish (US)
Pages (from-to)6546-6558
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number12
DOIs
StatePublished - Mar 18 2016

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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