Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation

Abstract

Eukaryotic cells express a family of eukaryotic translation initiation factor 2 alpha (eIF2alpha) kinases (eg, PKR, PERK-PEK, GCN2, HRI) that are individually activated in response to distinct types of environmental stress. Phosphorylation of eIF2alpha by one or more of these kinases reduces the concentration of eIF2-guanosine triphosphate (GTP)-transfer ribonucleic acid for methionine (tRNA(Met)), the ternary complex that loads tRNA(Met) onto the small ribosomal subunit to initiate protein translation. When ternary complex levels are reduced, the related RNA-binding proteins TIA-1 and TIAR promote the assembly of a noncanonical preinitiation complex that lacks eIF2-GTP-tRNA(Met). The TIA proteins dynamically sort these translationally incompetent preinitiation complexes into discrete cytoplasmic domains known as stress granules (SGs). RNA-binding proteins that stabilize or destabilize messenger RNA (mRNA) are also recruited to SGs during stress. Thus, TIA-1 and TIAR act downstream of eIF2alpha phosphorylation to promote SG assembly and facilitate mRNA triage during stress. The role of the SG in the integration of translational efficiency, mRNA stability, and the stress response is discussed.

Fig. 1.

Translational initiation in the absence or presence of stress. (A) Normal: when the eukaryotic translation initiation factor 2 (eIF2)–guanosine triphosphate (GTP)–transfer ribonucleic acid for methionine (tRNA^Met) ternary complex is available, a canonical 48S preinitiation complex is assembled at the 5′ end of capped transcripts and scanning begins. Upon recognition of the initiation codon by the anticodon of tRNA^Met, eIF5 promotes GTP hydrolysis, and early initiation factors are displaced by the 60S ribosomal subunit. (B) In stressed cells the phosphorylation of eIF2α prevents GDP-GTP exchange by eIF2B, which lowers the effective concentration of eIF2-GTP-tRNA^Met. Under these conditions, TIA-1 is included in a noncanonical preinitiation complex that is translationally silent. TIA-1 self-aggregation then promotes the accumulation of these complexes at discrete cytoplasmic foci known as stress granules

Fig. 2.

TIA-1 and TIAR are related ribonucleic acid (RNA)–binding proteins that possess 3 RNA-recognition motifs and a prion-related domain. Alternative splicing creates 2 isofoms of both proteins

Fig. 3.

Regulation of tumor necrosis factor α (TNFα) transcripts by TIA-1. An adenine-uridine–rich element (ARE) tethers TIA-1 to the 3′ untranslated region of TNFα transcripts. This increases the likelihood that TIA-1 will assemble at a noncanonical, translationally silent preinitiation complex, which delivers these transcripts to stress granules (SGs). The SG is proposed to function as a translational checkpoint that monitors mRNP composition and determines whether individual transcripts are stabilized or degraded. The ARE-binding proteins HuR and TTP are proposed to act downstream of the assembly of SGs to influence the functional fate of individual transcripts