Trends in Cell Biology
ReviewPrinciples and Properties of Stress Granules
Section snippets
RNP Granules
Various non-membrane-bound cellular compartments are termed RNP granules due to their high concentrations of protein and RNA. These include nuclear granules such as Cajal bodies, paraspeckles, and the nucleolus as well as cytoplasmic granules such as stress granules and processing bodies [1]. Other examples of RNP granules include neuronal granules and germ cell granules, which function in synaptic remodeling and maternal mRNA storage in early development 2, 3. RNP granules are generally
What Are Stress Granules?
Three observations suggest that stress granules represent assemblies of mRNPs stalled in translation initiation. First, stress granules form when translation initiation is inhibited either by drugs or by stress responses [4]. Similarly, stress granule-like RNP granules exist in neurons and embryos where there are significant pools of untranslating mRNPs [17]. Second, stress granules fail to form when mRNAs are trapped in polysomes, suggesting that mRNAs associated with ribosomes are unable to
Interactions Influencing Stress Granule Assembly
Stress granules assemble when untranslating mRNPs interact through protein–protein interactions between mRNA-binding proteins (Figure 2A). Analyses of the proteomes of yeast and mammalian stress granule cores identified a dense network of protein–protein interactions between stress granule components that could contribute in a redundant manner to stress granule formation [7]. For example, in both mammals and yeast, Atx2/Pbp1 or TIA1/Pub1 proteins promote but are not absolutely required for
Stress Granule Assembly: Possible Roles for Intrinsically Disordered Domains
Given the dynamic behavior of RNP granules in cells, and the behavior of RNP granule components in vitro, a current model is that many RNP granules are liquid–liquid phase separations (LLPSs) driven by dynamic and promiscuous interactions between IDRs 34, 39, 40, 41, 42. A LLPS occurs when a molecule or mixture of molecules forms a network of multivalent weak interactions that allow those molecules to concentrate into a separate phase. When applied to stress granules, this model for assembly
Multiple Phases of Stress Granule Assembly
One can identify multiple steps in stress granule assembly (Figure 3). In the most parsimonious model, nucleation occurs wherein we hypothesize the formation of oligomeric assemblies of untranslating mRNPs whose assembly can be controlled by post-translational modifications and/or RNP remodelers. For example, defects in the CCT chaperonin complex give more stress granules in yeast, which is consistent with the CCT complex limiting nucleation, either by remodeling interactions between mRNPs or
Dynamics, Disassembly, and Clearance of Stress Granules
Stress granules are dynamic structures and exhibit liquid-like behavior, rapid exchange rates of components, disassembly into translating mRNPs, and clearance by autophagy. Several lines of evidence now suggest a model where the dynamics of stress granules arise, at least in part, by ATP-dependent remodeling complexes. For example, acute pharmacological impairment of ATP production eliminates stress granule movement, fusion, and fission [7]. Moreover, ATP depletion increases the pools of G3BP
Functions of Stress Granules
Stress granule formation is expected to affect biological reactions in two ways. First, due to the high local concentration of components, the equilibria of interacting molecules will shift towards associated states. For example, during viral infections stress granules recruit numerous antiviral proteins including RIG-1, PKR, OAS, and RNaseL, stimulating their activation, and thereby enhance the induction of the innate immune response and viral resistance 67, 68, 69. Given this function, many
Stress Granules in Disease
Mutations that affect stress granule formation or persistence contribute to the formation of several degenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and some myopathies 15, 16. Strikingly, in many cases the mutations are in RNA-binding proteins (e.g., hnRNPA1, FUS, TDP-43, Atx2, TIA1), increasing their self-assembly properties in vitro and in cells leading to the formation of stress granule-like assemblies in the absence of stress.
Concluding Remarks
Stress granules are dynamic assemblies with yet to be fully appreciated roles in cell function (see Outstanding Questions). The interactions that drive their assembly appear complex and may include traditional protein–protein interactions as well as yet to be defined roles for IDRs. Stress granule dynamics, assembly, and disassembly are modulated by numerous post-translational modifications, RNP and protein remodeling complexes, and movement of components on microtubules, giving a complex set
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