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Translational control in stress and apoptosis

Nature Reviews Molecular Cell Biology volume 6, pages 318–327 (2005)Cite this article

Key Points

  • Translation is the final step in the flow of the genetic information, and regulation at this level allows an immediate, rapid and reversible response to changes in physiological conditions. This type of regulation is especially advantageous during conditions of cellular stress.

  • Translation is divided into three distinct phases: initiation, elongation and termination. Although all three phases are subject to regulatory mechanisms, under most circumstances the rate-limiting, regulated step is the initiation of translation.

  • Most cellular mRNAs are translated by a cap-dependent mechanism that involves the interaction of the 5′ m7G-cap structure of the mRNA with the cap-binding protein, eukaryotic initiation factor-4E (eIF4E), and the translation-initiation machinery. Some viral and cellular mRNAs have evolved a cap-independent mechanism of translation initiation that uses the internal ribosome-entry site (IRES) sequence that is located in the 5′ untranslated regions of these mRNAs. IRESs recruit ribosomes directly to the vicinity of the initiation codon without the requirement for eIF4E.

  • Global translation is reduced in response to most cellular stresses, both to conserve energy and to prevent the synthesis of unwanted proteins. Remarkably, the stress-induced attenuation of global translation is often accompanied by a switch to the selective translation of proteins that are required for cell survival under stress.

  • Several genes that are involved in cell growth and proliferation, differentiation and the regulation of apoptosis use IRES-mediated translation. This mode of translation provides a means for escaping the global decline in protein synthesis, and allows the selective translation of specific mRNAs, which indicates that the selective regulation of IRES-mediated translation is crucial to the regulation of cell death and survival.

Abstract

Cells respond to stress stimuli through coordinated changes in gene expression. The regulation of translation is often used under these circumstances because it allows immediate and selective changes in protein levels. There are many examples of translational control in response to stress. Here we examine two representative models, the regulation of eukaryotic initiation factor-2α by phosphorylation and internal ribosome initiation through the internal ribosome-entry site, which illustrate the importance of translational control in the cellular stress response and apoptosis.

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Figure 1: Cap-dependent versus internal ribosome-entry site-dependent translation initiation.
Figure 2: Integration of stress responses by the phosphorylation of eukaryotic initiation factor-2α.
Figure 3: RNA regulatory elements in the 5′ untranslated regions of mRNAs that are involved in selective translation.
Figure 4: Translational regulation of XIAP and APAF1 in apoptosis.

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Acknowledgements

We would like to thank members of our laboratories for critical reading of this manuscript and numerous discussions. The work in the laboratory of M.H. is supported by funds from the Canadian Institutes of Health Research (CIHR), Canada Foundation for Innovation, and the Natural Science and Engineering Research Council of Canada (NSERC). N.S. is supported by funds from the CIHR, National Cancer Institute of Canada, National Institutes of Health and Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Apoptosis Research Center, Room R3116, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, K1H 8L1, ON, Canada

    Martin Holcik

  2. Department of Biochemistry and McGill Cancer Center, McGill University, McIntyre Medical Sciences Building, Room 807, 3655 Drummond Street, Montreal, H3G 1Y6, PQ, Canada

    Nahum Sonenberg

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  1. Martin Holcik
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DATABASES

OMIM

Wolcott–Rallison syndrome

Swiss-Prot

APAF1

ATF4

FGF2

GCN2

GCN4

GRP78

HIF1

HTRA2

PAIP1

PDGF2

PIM1

UNR

FURTHER INFORMATION

IRES Database

Glossary

ENDOPLASMIC RETICULUM (ER) STRESS

Perturbations of the ER function that are caused by the accumulation of misfolded proteins, oxidative stress, inhibition of glycosylation or alteration in Ca2+ homeostasis.

INTERNAL RIBOSOME-ENTRY SITE

(IRES). A ribosome-binding site that is found in the 5′ UTR or in a coding region of a few cellular and viral RNAs. The IRES facilitates translation by recruiting ribosomes directly to the mRNA independently of the cap structure.

BICISTRONIC mRNA

Allows two different proteins to be translated from the same mRNA strand; the first protein is usually translated by a cap-dependent mechanism, whereas the second protein is translated through an IRES.

RNA CHAPERONE

An RNA-binding protein that aids the correct folding of a given RNA.

UPSTREAM OPEN READING FRAME

(uORF). A short reading frame that is located in the 5′ UTR of some mRNAs. Certain uORFs code for short polypeptides, whereas others are non-coding.

UNFOLDED PROTEIN RESPONSE

(UPR). A coordinated adaptive programme that is triggered by ER stress. The UPR leads to the inhibition of global protein synthesis, and the selective transcription and translation of proteins, which helps the cell to deal with ER stress.

BASIC-HELIX-LOOP-HELIX (bHLH)–LEUCINE-ZIPPER (ZIP) FAMILY

Transcription factors that have a bHLH DNA-binding motif and a zip dimerization motif, which regulate the expression of their target genes as hetero- or homodimers.

POLYSOME

An mRNA with more than one associated translating 80S ribosome.

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Holcik, M., Sonenberg, N. Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 6, 318–327 (2005). https://doi.org/10.1038/nrm1618

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