Review
Stress granules and cell signaling: more than just a passing phase?

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Highlights

  • Stress granule assembly may involve a demixing phase transition.

  • Intrinsically disordered motifs may promote recruitment to stress granules.

  • Stress granules may function as RNA-centric signaling hubs.

Stress granules (SGs) contain translationally-stalled mRNAs, associated preinitiation factors, and specific RNA-binding proteins. In addition, many signaling proteins are recruited to SGs and/or influence their assembly, which is transient, lasting only until the cells adapt to stress or die. Beyond their role as mRNA triage centers, we posit that SGs constitute RNA-centric signaling hubs analogous to classical multiprotein signaling domains such as transmembrane receptor complexes. As signaling centers, SG formation communicates a ‘state of emergency’, and their transient existence alters multiple signaling pathways by intercepting and sequestering signaling components. SG assembly and downstream signaling functions may require a cytosolic phase transition facilitated by intrinsically disordered, aggregation-prone protein regions shared by RNA-binding and signaling proteins.

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

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