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Review
. 2019 May 1;11(5):a032813.
doi: 10.1101/cshperspect.a032813.

Stress Granules and Processing Bodies in Translational Control

Pavel Ivanov  1   2   3 , Nancy Kedersha  1   2 , Paul Anderson  1   2
Affiliations
Review

Stress Granules and Processing Bodies in Translational Control

Pavel Ivanov et al. Cold Spring Harb Perspect Biol. .

Abstract

Stress granules (SGs) and processing bodies (PBs) are non-membrane-enclosed RNA granules that dynamically sequester translationally inactive messenger ribonucleoprotein particles (mRNPs) into compartments that are distinct from the surrounding cytoplasm. mRNP remodeling, silencing, and/or storage involves the dynamic partitioning of closed-loop polyadenylated mRNPs into SGs, or the sequestration of deadenylated, linear mRNPs into PBs. SGs form when stress-activated pathways stall translation initiation but allow elongation and termination to occur normally, resulting in a sudden excess of mRNPs that are spatially condensed into discrete foci by protein:protein, protein:RNA, and RNA:RNA interactions. In contrast, PBs can exist in the absence of stress, when specific factors promote mRNA deadenylation, condensation, and sequestration from the translational machinery. The formation and dissolution of SGs and PBs reflect changes in messenger RNA (mRNA) metabolism and allow cells to modulate the proteome and/or mediate life or death decisions during changing environmental conditions.

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Figures

Figure 1.
Figure 1.
Selected stress granule (SG)- and processing body (PB)-associated proteins. Proteins (partial list) found exclusively in SGs (blue box), in both SGs and PB/GW-bodies (GWBs) (green box), or predominantly in PB/GWBs (red box). Image obtained using arsenite-treated U2OS cells stained for eukaryotic initiation factor 3b (eIF3b) (blue), DCP1a (red), and eIF4E (green).
Figure 2.
Figure 2.
Stress granule (SG) nucleation, eukaryotic initiation factor 2α (eIF2α) phosphorylation, and global translation. Transient expression of (A) SG-nucleating proteins T-cell intracellular antigen 1 (TIA1), or (B) FMRP autosomal homolog 1 (FXR1) in COS7 cells triggers eIF2α phosphorylation (red) and prevents translation (blue in merged figure, shown separately in gray), as shown by labeling with the amino acid analog l-azidohomoalanine (AHA) in some transfectants (white arrows) but not those lacking SGs (green arrow). Overexpression of GTP-activating protein-binding protein 1 (G3BP1) (C,D) can nucleate SGs before/without triggering eIF2α phosphorylation or translational arrest (green arrows). Yellow indicates red/green colocalization.
Figure 3.
Figure 3.
Regulatory stalling points in the translational cycle leading to stress granule (SG) formation. A closed-loop messenger RNA (mRNA) can stall at different points in the translation cycle, resulting in messenger ribonucleoproteins (mRNPs) of different composition eligible for condensation (mediated by GTP-activating protein-binding protein 1 [G3BP]) into SGs. Type I, or canonical SGs, result when eukaryotic initiation factor 2α (eIF2α) phosphorylation inhibits recharging of eIF2•GTP-Met-tRNAi Met, resulting in mRNPs that lack eIF2/5. Type II SGs form when eIF4A activities are inhibited and can be induced in cells lacking phospho-eIF2α, generating SGs that contain eIF2/5. Type III SGs result from xenobiotic stress, and lack eIF3. The mechanism shown here is hypothetical. Not shown are hyperosmotic/G3BP-independent SGs thought to arise from molecular crowding.
Figure 4.
Figure 4.
Relationship between polysomes, stress granules (SGs), and processing bodies (PBs). Polysomes are maintained when translation initiation and termination occur at balanced rates on a single messenger RNA (mRNA). When termination occurs more frequently than initiation, polysome disassembly results, resulting in stalled, circularized messenger ribonucleoproteins (mRNPs). Agents that prevent elongation (such as emetine and cycloheximide) inhibit polysome/mRNP conversion, and hence reduce the pool of mRNPs, whereas puromycin promotes premature termination and accelerates the polysome-mRNP conversion. A pool of free mRNPs is necessary, but not sufficient, for SG assembly, which requires the dynamic condensation of mRNPs out of the surrounding cytoplasm. Condensation (and possibly decondensation) requires the mRNA-binding protein G3BP, and is regulated by G3BP-binding proteins Caprin1 (which promotes) and USP10 (which inhibits) the G3BP-mediated condensation of mRNPs into SGs. PBs contain deadenylated mRNPs and/or mRNAs undergoing deadenylation, and PB condensation requires multiple proteins, including EDC4, LSM14, 4-ET, and DDX6 (reviewed in Luo et al. 2018).
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