RNA-Binding Proteins Tia-1 and Tiar Link the Phosphorylation of Eif-2α to the Assembly of Mammalian Stress Granules

TLDR

In response to stress, RNA‑binding proteins TIA‑1 and TIAR co‑localize with poly(A)+ RNA in cytoplasmic foci resembling stress granules, where accumulation of untranslated mRNA is reversible after sublethal stress but irreversible after lethal stress. Phosphorylation of eIF‑2α initiates TIA‑1/TIAR‑dependent stress granule assembly, with phosphomimetic eIF‑2α inducing SGs, nonphosphorylatable eIF‑2α preventing them, and a TIA‑1 RNA‑binding‑deficient mutant acting as a trans‑dominant inhibitor, indicating that TIA‑1 functions downstream of eIF‑2α phosphorylation to sequester untranslated mRNAs and that SG dynamics may regulate the duration of stress‑induced translational arrest. Citations include Nover et al.

Abstract

In response to environmental stress, the related RNA-binding proteins TIA-1 and TIAR colocalize with poly(A)(+) RNA at cytoplasmic foci that resemble the stress granules (SGs) that harbor untranslated mRNAs in heat shocked plant cells (Nover et al. 1989; Nover et al. 1983; Scharf et al. 1998). The accumulation of untranslated mRNA at SGs is reversible in cells that recover from a sublethal stress, but irreversible in cells subjected to a lethal stress. We have found that the assembly of TIA-1/R(+) SGs is initiated by the phosphorylation of eIF-2alpha. A phosphomimetic eIF-2alpha mutant (S51D) induces the assembly of SGs, whereas a nonphosphorylatable eIF-2alpha mutant (S51A) prevents the assembly of SGs. The ability of a TIA-1 mutant lacking its RNA-binding domains to function as a transdominant inhibitor of SG formation suggests that this RNA-binding protein acts downstream of the phosphorylation of eIF-2alpha to promote the sequestration of untranslated mRNAs at SGs. The assembly and disassembly of SGs could regulate the duration of stress- induced translational arrest in cells recovering from environmental stress.