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, 215 (3), 313-323

Mechanistic Insights Into Mammalian Stress Granule Dynamics


Mechanistic Insights Into Mammalian Stress Granule Dynamics

Marc D Panas et al. J Cell Biol.


The accumulation of stalled translation preinitiation complexes (PICs) mediates the condensation of stress granules (SGs). Interactions between prion-related domains and intrinsically disordered protein regions found in SG-nucleating proteins promote the condensation of ribonucleoproteins into SGs. We propose that PIC components, especially 40S ribosomes and mRNA, recruit nucleators that trigger SG condensation. With resolution of stress, translation reinitiation reverses this process and SGs disassemble. By cooperatively modulating the assembly and disassembly of SGs, ribonucleoprotein condensation can influence the survival and recovery of cells exposed to unfavorable environmental conditions.


Figure 1.
Figure 1.
Model of canonical and noncanonical PIC formation under various conditions. Note that the diagram is not time resolved, and hence some depicted interactions may not occur simultaneously or be competitive. (A) Assembly of the 48S PIC during normal conditions. The ternary complex joins the 40S ribosomal subunit and forms a 43S preinitiation complex. The eIF4F complex (eIF4E, eIF4A, and eIF4G) binds together with eIF4B to the 5′ cap of the mRNA. The eIF4F-bound mRNA associates with the 43S PIC, and then scans to the AUG start codon, where 48S PIC formation occurs. (B) Formation of noncanonical PICs during various stress conditions. Here, we depict three different signaling pathways that assemble noncanonical PICs: (1) mTOR inhibition by sodium selenite, amino acid (AA) starvation, rapamycin, or oxidative stress (H2O2), which leads to hypophosphorylation of 4E-BP, which then interacts with eIF4E and blocks translation initiation; (2) various stresses activate distinct eIF2α kinases that phosphorylate eIF2α, deplete the ternary complex, and promote the assembly of a noncanonical PIC; and (3) compounds such as pateamine A, 15-deoxy-Δ(12,14)-prostaglandin J2 (15d PGJ2), hippuristanol, silvestrol, or tiRNA target the eIF4F complex, also creating a noncanonical PIC. These noncanonical PICs differ from canonical PICs in composition and exposure of the 40S subunit interface and mRNA. These interfaces recruit RNA-BPs such as G3BP and TIA-1/R, increasing the local concentration of these proteins to promote LLPS and assembly of SG seeds. Figure modified from Jackson et al. (2010).
Figure 2.
Figure 2.
Human 40S ribosomal proteins containing disordered regions. (A) Images based on the crystal structure of the human 40S ribosomal subunit (protein database: 4UG0; Khatter et al., 2015). Views from the 40S subunit solvent site (left), 40S subunit interface site (middle), and mRNA exit site (right). Disordered 40S ribosomal proteins at the mRNA entry sites (left and middle) are uS2 (red), uS5 (violet), eS21 (green), and eS30 (blue). Disordered 40S ribosomal proteins, which are located at the platform and close to the mRNA exit site, include uS7 (light blue), eS17 (dark red), eS26 (dark blue), and eS28 (orange). Ribosomal RNA and other 40S ribosomal proteins are shown in light gray. (B) Schematic representation of IDPRs in 40S ribosomal subunit proteins. The disordered regions are from the protein database website. The disorder calculations are based on the JRONN method (Yang et al., 2005). Red, potentially disordered; blue, potentially ordered. Shown are the nomenclature of small ribosomal subunit names, the amino acid length, and the potentially disordered regions.
Figure 3.
Figure 3.
Model of SG assembly and disassembly. (A) Once nanoscopic SG seeds are formed (Fig. 1 B), nearby seeds attract each other via weak electrostatic interactions, interact with neighboring SG seeds, and coalescence to form irregular microscopically visible SGs. Microscopically visible SGs can fuse to produce larger SGs. (B) After stress release, events that promote SG disassembly may include increase in concentrations of ternary complexes; phosphorylation of 4E-BP by mTOR, releasing the eIF4E block; and reactivation of eIF4A activities. These events might trigger the formation of translationally competent PICs to reinitiate translation at the surface of SGs. Because translating ribosomes displace mRNA-bound RNA-BPs, those complexes are then detached from SGs. As SGs shrink, the Laplace pressure increases to promote further fusion with adjacent SGs. Over time, fewer and larger SGs appear before they eventually disappear from the cytoplasm. Other SG proteins such as USP10 can potentiate disassembly by maintaining G3BP in a soluble conformation. PTM of ribosomal and SG proteins might also contribute to the disassembly.

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