Stress granules: the Tao of RNA triage

doi:10.1016/j.tibs.2007.12.003

Trends in Biochemical Sciences

Volume 33, Issue 3, March 2008, Pages 141-150

https://doi.org/10.1016/j.tibs.2007.12.003 Get rights and content

Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay.

Section snippets

mRNA triage: reprogramming translation during stress

Post-transcriptional regulation of gene expression is crucial for development, differentiation, immune signaling and neuronal plasticity [1]. mRNA biogenesis and function require the concerted efforts of RNA-binding proteins that shepherd the mRNA transcript through its capping, splicing, polyadenylation, nuclear export, association with ribosomes and ultimate decay [2]. Stresses (see Glossary), such as heat shock, oxidative stress, ischemia or viral infection, trigger a sudden translational

SGs and PBs: kissing cousins

SGs are closely related to a second class of RNA granule known as the PB or GW182-containing body (GW body) 11, 12. Both PBs and SGs are simultaneously assembled in cells subjected to environmental stress 13, 14, both are assembled on untranslated mRNA derived from disassembled polysomes, and both contain a subset of shared proteins including FAST (Fas-activted serine/threonine kinase), XRN1 (5′–3′ exoribonuclease 1), eukaryotic translation initiation factor 4E (eIF4E), tristetraprolin (TTP),

The eIF2α kinases: cellular stress sensors

The integrated stress response comprises a series of changes in cellular metabolism that enable the cell to repair stress-induced damage and survive adverse environmental conditions. Noxious conditions (e.g. excess heat, oxidation, UV irradiation, viral infection) induce eukaryotic cells to halt protein synthesis in a stereotypic response that conserves anabolic energy for the repair of molecular damage. The translational arrest that accompanies environmental stress is potentially selective:

SG protein composition and classification: who's in and who's out

SG components include a diverse group of mRNAs and proteins, some with no previously known links to RNA metabolism (Table 1). The first and defining class of SG components consists of stalled initiation complexes, still bound to mRNA and recruited to SGs from disassembling polysomes. This class includes mRNA transcripts, eIF3, eIF4F (comprising eIF4E, eIF4A and eIF4G), eIF4B, small ribosomal subunits and PABP-1 3, 32. These core SG components are universal markers for all SGs.

A second class of

SG-associated mRNAs

Less is known about which specific mRNA transcripts are included in or exempt from SG recruitment. Although only 50% of cytoplasmic poly(A) RNA and poly(A)-binding protein-1 is recruited to SGs, nearly 90% of TIA-1 is recruited to SGs; this indicates that the mRNA content of SGs is selective [3]. Endogenous cellular mRNAs encoding glyceraldehyde-3-phosphate dehydrogenase (GAPDH), β-actin, c-MYC, insulin-like growth factor II (IGF-II) and H19 are quantitatively recruited to SGs [41], whereas

Stages of SG assembly

SG assembly links stalled initiation, polysome disassembly and mRNP aggregation in a series of reversible stages (Figure 1). Even when fully formed, SGs continue to sort their mRNP contents, routing them to other cellular sites and fates.

Regulated aggregation events in SG assembly and dynamics

Most proteins that nucleate SG assembly contain domains that bind to RNA directly, in addition to distinct domains that mediate homotypic aggregation. TIA-1 and TIAR possess glutamine-rich PRDs at their carboxyl termini [60], which are essential for SG assembly. When expressed in COS-7 cells, full-length recombinant TIA-1 nucleates the assembly of bona fide SGs, whereas recombinant TIA-1 lacking the PRD does not [60]. The PRD from the well-characterized yeast translation termination factor

SGs in infection and disease

SGs might participate in life-or-death decisions in stressed cells by selectively regulating the expression of proteins involved in cell survival. The duration of SG-mediated reprogramming of mRNA translation and decay beyond a critical threshold can activate apoptosis. Indeed, many viruses regulate the assembly or disassembly of SGs 59, 67, 68, 69, 70 (Box 2), suggesting their importance in balancing the translation of host- and virus-encoded mRNAs. SGs have also been implicated in disease

Concluding remarks and future perspectives

There is an emerging consensus that translation initiation is in dynamic equilibrium with an active process of translational silencing. In growing somatic cells, the rate of translation initiation exceeds the rate of translation silencing and most, but not all, cytoplasmic mRNA is located in polysomes [32]. Cellular stress shifts this equilibrium such that the silencing rate exceeds the initiation rate. Many SG components mediate the translational silencing of virgin mRNA transcripts during

Acknowledgements

We thank Dan Schoenberg and Georg Stoecklin for critical review of the manuscript. Work in our laboratories is supported by grants from the National Institutes of Health and the American College of Rheumatology. We regret that we were unable to cite many relevant papers due to size limitations.

Glossary

ARE: AU-rich element; an RNA domain, found at the 3′ end of many mRNAs, that promotes silencing or decay.
Argonaute (Ago): a family of proteins associated with microRNAs, containing both a PIWI domain and a PAZ (Piwi Argonaute Zwille) domain. A subset of Argonaute proteins possess endonuclease ‘slicer’ activity and cleave mRNA, whereas others only silence translation.
eIF2α: a regulatory subunit of the eukaryotic translation initiation factor 2 (eIF2) complex, which is part of a larger ternary complex

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Trends in Biochemical Sciences

ReviewStress granules: the Tao of RNA triage

Section snippets

mRNA triage: reprogramming translation during stress

SGs and PBs: kissing cousins

The eIF2α kinases: cellular stress sensors

SG protein composition and classification: who's in and who's out

SG-associated mRNAs

Stages of SG assembly

Regulated aggregation events in SG assembly and dynamics

SGs in infection and disease

Concluding remarks and future perspectives

Acknowledgements

Glossary

Trends Biochem. Sci.

Cell

Mol. Cell

Mol. Cell

J. Biol. Chem.

Mol. Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Mol. Cell

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Methods Enzymol.

Mol. Cell

Cell Host Microbe

Cancer Cell

Curr. Opin. Genet. Dev.

Neuroscience

Resuscitation

Neuroscience

Trends Genet.

From birth to death: the complex lives of eukaryotic mRNAs

Science

Stressful initiations

J. Cell Sci.

RNA granules

J. Cell Biol.

Sequestration of TRAF2 into stress granules interrupts tumor necrosis factor signaling under stress conditions

Mol. Cell. Biol.

FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression

Mol. Cell. Biol.

Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules

Proc. Natl. Acad. Sci. U. S. A.

MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies

Nat. Cell Biol.

P bodies: at the crossroads of post-transcriptional pathways

Nat. Rev. Mol. Cell Biol.

The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules

J. Cell Sci.

Stress granules and processing bodies are dynamically liked sites of mRNP remodeling

J. Cell Biol.

Accumulation of polyadenylated mRNA, Pab1p, eIF4E, and eIF4G with P-bodies in Saccharomyces cerevisiae

Mol. Biol. Cell

Stress-dependent relocalization of translationally primed mRNPs to cytoplasmic granules that are kinetically and spatially distinct from P-bodies

J. Cell Biol.

Decapping and decay of messenger RNA occur in cytoplasmic processing bodies

Science

Global mRNA stabilization preferentially linked to translational repression during the endoplasmic reticulum stress response

Mol. Cell. Biol.

The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids

Mol. Cell. Biol.

Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2.GTP.Met-tRNA(i)(Met) ternary complex availability

Mol. Biol. Cell

Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules

J. Cell Biol.

Inhibition of ribosome recruitment induces stress granule formation independently of eukaryotic initiation factor 2alpha phosphorylation

Mol. Biol. Cell

Review
Stress granules: the Tao of RNA triage