Principles and Properties of Stress Granules

Abstract

Stress granules are assemblies of untranslating messenger ribonucleoproteins (mRNPs) that form from mRNAs stalled in translation initiation. Stress granules form through interactions between mRNA-binding proteins that link together populations of mRNPs. Interactions promoting stress granule formation include conventional protein-protein interactions as well as interactions involving intrinsically disordered regions (IDRs) of proteins. Assembly and disassembly of stress granules are modulated by various post-translational modifications as well as numerous ATP-dependent RNP or protein remodeling complexes, illustrating that stress granules represent an active liquid wherein energy input maintains their dynamic state. Stress granule formation modulates the stress response, viral infection, and signaling pathways. Persistent or aberrant stress granule formation contributes to neurodegenerative disease and some cancers.

Keywords: RNP granule; intrinsically disordered protein; phase separation; stress granule.

Figure 1. Stress Granules are dynamic and have multiple fates

Stress granules form from untranslating mRNPs. They can interact with P-bodies, exchange components with the cytoplasm, and undergo autophagy.

Figure 2. Intermolecular interactions that drive stress granule assembly

A) A diverse set of intermolecular interactions are important for granule assembly. B) Various mechanisms by which intrinsically disordered regions could contribute to granule assembly.

Figure 3. Two models for discrete phases of stress granule assembly

Stress granules can by hypothesized to undergo three phases of assembly. A) In the “Cores First” model, cores precede assembly of large stress granules. The first phase of assembly is the nucleation of translationally repressed RNPs into oligomers. The second phase of assembly is growth of these oligomers into larger assemblies by addition of more translationally repressed RNPs. The third phase of assembly is fusion of these core assemblies and recruitment of the dynamic shell to form the large, microscopically visible granules typically observed in cells. Some of the stability of cores may be due to amyloid interactions, as indicated by squiggly red lines. B) In the “LLPS First” model, the formation of large stress granules precedes core assembly. The first phase of this model is the nucleation of translationally repressed RNPs into initial phase separated droplets, held together by weak dynamics interactions. The second phase is growth of initial droplets by the addition of translationally repressed RNPs. The third phase of assembly is core formation within phase separated granules due to the high local concentration of proteins within the droplets. In this model, the formation of cores may be driven in part by amyloid interactions, as indicated by squiggly red lines.

Figure 4. Various ATPases impact granule assembly

Heat shock proteins, helicases, and VCP all impact stress granule assembly by remodeling specific interactions utilizing the energy of ATP hydrolysis.