Fig. 2 |. Formation of stress granules from the mRNA–ribosomal complex.
Multiple steps are involved in the transition from a translated mRNA to a primary nucleated stress granule. a | Initially, the mRNA associates with the 40S ribosomal particle to form the pre-initiation complex (PIC). b | The PIC complex then combines with the 60S ribosome particle to form the 80S ribosome, which actively translates mRNA to make proteins. The antibiotics cycloheximide and puromycin are commonly used to study stress granule (SG) biology and exert opposite actions; cycloheximide prevents SG formation whereas puromycin promotes SG formation. c | Cycloheximide acts by stalling translation elongation by inhibiting ribosome translocation, which ‘freezes’ the mRNA covered by ribosomes and hidden from RNA-binding proteins (RBPs) in the cytoplasm, whereas puromycin breaks up the translating ribosomes by becoming incorporated into the nascent polypeptide chain, and causing separation of the 60S ribosomal subunit from the 40S–mRNA complex. d | The free mRNA–40S complex associates with core nucleating RNA-binding proteins (RBPs), such as T-cell intracellular antigen 1 (TIA1), RAS GTP-activating protein-binding protein 1 (G3BP1), TIA1-related protein (TIAR), tristetraprolin (TTP) and cytoplasmic activation/proliferation-associated protein 1 (CAPRIN). e | Stimulated by the presence of mRNAs and RBPs (and likely other factors, such as post-translational modifications), mRNA–RBP complexes begin coalescing to become primary SGs through the process of liquid–liquid phase separation. Note that polysomes and SGs exist in an equilibrium, which is regulated by the cell state (not shown).