Trends in Biochemical Sciences
ReviewStress granules and cell signaling: more than just a passing phase?
Section snippets
SG assembly
Mammalian SGs were first described as cytoplasmic, nonmembranous, phase-dense structures assembled in response to the stress-induced phosphorylation of eukaryotic initiation factor (eIF)2α) [1], the central trigger of the integrated stress response (ISR) [2]. Key features of the ISR are translational arrest, polysome disassembly, and SG assembly, which enable the cell to reprogram its translational repertoire via a process dubbed mRNA triage [2]. Most SG components exhibit short residence times
Protein-interaction domains promote SG assembly
An early insight into the molecular mechanism controlling the aggregation and localization of untranslated mRNPs into SGs came from studies of the RNA-binding protein TIA-1, which contains a prion-related domain. This Q/N-rich motif of low amino acid complexity resembles that found in the aggregation domain of prion protein, mediates the reversible cytoplasmic aggregation of untranslated mRNPs [20], and can be functionally replaced with the aggregation domain from the yeast prion Sup35.
Recruitment of signaling proteins to SGs
The concentration-dependent aggregation of multivalent signaling proteins promotes a demixing phase transition from a soluble to an immiscible liquid state in vitro and in vivo [40]. This process effectively segregates selected proteins from the cytosol, creating a circumscribed domain whose physical properties are distinct from that of the bulk cytosol. The LC/ID regions common to SG-associated RNA-binding proteins and signaling molecules suggest RNA granules may result from similar
RACK1/p38/JNK signaling
RACK1 is a pleiotropic adaptor protein that integrates cell adhesion, polarity, and motility [51]. Although it lacks LC/ID regions, it is an integral part of the small 40S ribosomal subunit and binds the multisubunit eIF3 complex; both of these are core SG constituents. The sequestration of RACK1 at SGs inhibits the stress-induced activation of the p38/JNK signaling cascade that triggers apoptotic death [52]. RACK1 serves as a scaffold that multimerizes MTK1, a mitogen-activated protein kinase
ISR/phospho-eIF2α signaling
In mammalian cells, SG assembly is predominantly initiated by stress-induced phosphorylation of eIF2α, especially in response to viral infection [18]. OGFOD1 (2-oxoglutarate and Fe(II)-dependent oxygenase domain containing) is an SG-nucleating protein that interacts (directly or indirectly) with the SG proteins G3BP, USP10, caprin1, (Y-box binding protein) YB-1, HRI kinase, and its substrate eIF2α [53]. OGFOD1 expression levels correlate with both phosphorylation of eIF2α and SG assembly,
Target of rapamycin (TOR) signaling
The conserved kinase TOR assembles two distinct complexes (TORC1 and TORC2) that control cellular growth and metabolism [54]. SG assembly in both yeast and human cells alters TORC1 signaling by sequestering both TORC1 and downstream kinases to alter signaling during stress 55, 56. Under optimal growth conditions, signals from growth factor receptors and environmental nutrients conspire to keep TORC1 active at vacuolar or lysosomal membranes [54], allowing TORC1 to promote protein synthesis and
Rho GTPase signaling
Rho GTPases modulate various aspects of vesicle trafficking, cell cycle progression, and cytoskeletal rearrangement 61, 62, 63. Upon activation, Ras homolog gene family member A (RhoA) binds and activates its downstream kinase, Rho-associated, coiled-coil containing protein kinase (ROCK)1. ROCK1 in turn phosphorylates JNK-interacting protein (JIP)-3, resulting in activation of JNK and induction of apoptosis [64]. Just as sequestration of RACK1 at SGs prevents JNK-induced apoptosis,
Concluding remarks
The evolving phase transition model of RNA granules describes a fluid-like conglomeration of RNA and disordered RNA-binding proteins that comprise the ‘dark matter’ of RNA granules; that is, the missing component that gives both stable (germ cell granules) and dynamic (SGs and PBs) RNA granules their form and physical properties. This model proposes that RNA granules form when fleeting and multiple low-affinity interactions between ID/LC-containing proteins promote a demixing phase transition
Glossary
- 14-3-3 proteins
- A family of ∼30-kDa adaptor proteins that bind to phosphoserine or phoshothreonine residues on diverse signaling proteins resulting in altered subcellular localization and/or function.
- Demixing phase transition
- the transformation of a material from one physical state to another. LC/ID region-containing proteins are proposed to undergo phase transitions in the cell, where they condense from a diffuse, soluble state into a concentrated liquid-droplet phase (or aggregate into
References (112)
Stress granules: the Tao of RNA triage
Trends Biochem. Sci.
(2008)Regulated translation initiation controls stress-induced gene expression in mammalian cells
Mol. Cell
(2000)Perk is essential for translational regulation and cell survival during the unfolded protein response
Mol. Cell
(2000)Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA- dependent protein kinase
J. Biol. Chem.
(1998)Stress granules contribute to alpha-globin homeostasis in differentiating erythroid cells
Biochem. Biophys. Res. Commun.
(2012)Heme-regulated inhibitor (HRI) kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 (eIF2) inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure
J. Biol. Chem.
(2005)Eukaryotic initiation factor 2alpha-independent pathway of stress granule induction by the natural product pateamine A
J. Biol. Chem.
(2006)- et al.
Regulation of stress granules in virus systems
Trends Microbiol.
(2012) Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies
Cell
(2012)Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels
Cell
(2012)
Protein disorder, prion propensities, and self-organizing macromolecular collectives
Biochim. Biophys. Acta
Unusual biophysics of intrinsically disordered proteins
Biochim. Biophys. Acta
Analysis of compositionally biased regions in sequence databases
Methods Enzymol.
Getting RNA and protein in phase
Cell
Interaction with 14-3-3 adaptors regulates the sorting of hMex-3B RNA-binding protein to distinct classes of RNA granules
J. Biol. Chem.
Insights into RNA biology from an atlas of mammalian mRNA-binding proteins
Cell
Prediction and functional analysis of native disorder in proteins from the three kingdoms of life
J. Mol. Biol.
Beyond ‘furballs’ and ‘dumpling soups’ – towards a molecular architecture of signaling complexes and networks
FEBS Lett.
Amino acids and mTORC1: from lysosomes to disease
Trends Mol. Med.
Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling
Cell
Transient sequestration of TORC1 into stress granules during heat stress
Mol. Cell
The TOR complex 1 is a direct target of Rho1 GTPase
Mol. Cell
AMPK phosphorylation of raptor mediates a metabolic checkpoint
Mol. Cell
PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase
Mol. Cell
Signaling networks of Rho GTPases in cell motility
Cell. Signal.
Rho GTPases and their roles in cancer metabolism
Trends Mol. Med.
RhoA/ROCK1 signaling regulates stress granule formation and apoptosis
Cell. Signal.
Dishevelled: the hub of Wnt signaling
Cell. Signal.
Macromolecular crowding regulates assembly of mRNA stress granules after osmotic stress: new role for compatible osmolytes
J. Biol. Chem.
Eukaryotic stress granules: the ins and outs of translation
Mol. Cell
Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival
Mol. Cell
A single mutation converts a novel phosphotyrosine binding domain into a dual-specificity phosphatase
J. Biol. Chem.
Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains
Trends Biochem. Sci.
Recruitment of the RNA helicase RHAU to stress granules via a unique RNA-binding domain
J. Biol. Chem.
The DEAD-box protein Ded1 modulates translation by the formation and resolution of an eIF4F-mRNA complex
Mol. Cell
Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm
Mol. Cell
Angiogenin-induced tiRNAs promote stress-induced stress granule assembly
J. Biol. Chem.
Angiogenin-induced tRNA fragments inhibit translation initiation
Mol. Cell
Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation
Immunity
Roquin-2 shares functions with its paralog roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation
Immunity
Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs
Cell
Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress
J. Biol. Chem.
RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2α to the assembly of mammalian stress granules
J. 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.
Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses
Mol. Cell. Biol.
Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules
Mol. Biol. Cell
Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes
Am. J. Physiol. Cell Physiol.
Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules
J. Cell Biol.
Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation
Proc. Natl. Acad. Sci. U.S.A.
A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly
Nat. Cell Biol.
Cited by (469)
A regulatory module comprising G3BP1-FBXL5-IRP2 axis determines sodium arsenite-induced ferroptosis
2024, Journal of Hazardous MaterialsStress granules and hormetic adaptation of cancer
2023, Trends in CancerRole of stress granules in tumorigenesis and cancer therapy
2023, Biochimica et Biophysica Acta - Reviews on Cancer