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Comment
. 2011 Oct 15;25(20):2119-24.
doi: 10.1101/gad.17838411.

Stress puts TIA on TOP

Pavel Ivanov  1 , Nancy Kedersha, Paul Anderson
Affiliations
Comment

Stress puts TIA on TOP

Pavel Ivanov et al. Genes Dev. .

Abstract

Under conditions of limited nutrients, eukaryotic cells reprogram protein expression in a way that slows growth but enhances survival. Recent data implicate stress granules, discrete cytoplasmic foci into which untranslated mRNPs are assembled during stress, in this process. In the October 1, 2011, issue of Genes & Development, Damgaard and Lykke-Andersen (p. 2057-2068) provide mechanistic insights into the regulation of a specific subset of mRNAs bearing 5'-terminal oligopyrimidine tracts (5'TOPs) by the structurally related stress granule proteins TIA-1 and TIAR.

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Figures

Figure 1.
Figure 1.
Translation of TOP mRNAs under conditions of active growth versus starvation. (Active/Growth) Under nutrient-rich conditions, translation of TOP mRNAs is initiated when the cap-binding eIF4F complex (eIF4E/G/A) binds to the m7G cap and recruits the activated 43S complex (40S subunit, eIF1, eIF1A, eIF3, and eIF2–GTP–tRNAiMet/eIF5) to assemble the 48S preinitiation complex. (Top shaded area) The assembly of the eIF2–GTP–tRNAiMet ternary complex associated with eIF5 is a key regulatory event requiring the eIF2B-mediated activation of eIF2 by GDP–GTP exchange and recruitment of tRNAiMet. Translation is enhanced by miR-10a binding to sequences downstream from the 5′TOP motif, which may prevent the inhibitory effect of TIA-1/R binding to the TOP motif. (Repressed/Starvation) Under amino acid starvation conditions, Damgaard and Lykke-Andersen (2011) show that TIA-1/R is recruited to the 5′TOP motif to prevent the assembly of the canonical 48S preinitiation complex. (Shaded area at right) TIA-1/R:5′TOP binding appears to require the GCN2-mediated phosphorylation of eIF2α, which prevents GDP/GTP exchange and subsequent charging of the eIF2:eIF5 complex with tRNAiMet. Formation of noncanonical 48S complexes lacking the charged ternary complex (48S*) may facilitate TIA-1/R binding to the 5′TOP motif and thereby repress initiation. In non-TOP mRNAs, TIA-1/R can bind to U-rich elements in the 3′ UTR (hairpin [HP], C-rich element [CRE]; and adenine/uridine-rich element [ARE]) to inhibit translation initiation by an uncharacterized mechanism. Damgaard and Lykke-Andersen (2011) also implicate mTOR inactivation in the TIA-1/R-mediated repression of TOP mRNA translation. (Gray area at left) A possible mechanism is shown wherein mTOR inactivation results in dephosphorylation of 4EBP and consequent disruption of eIF4G:eIF4E interactions. TIA-1/R-inactivated 48S* complexes are assembled into stress granules (SGs) for mRNA triage and possible cross-talk with other signaling pathways.
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