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Stressful initiations

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA

View larger version (65K): [in a new window]   Fig. 1. Assembly and disassembly of arsenite-induced stress granules. DU145 cells were cultured in the absence (control) or presence of arsenite (1 mM) for 30 minutes (STRESS), washed and allowed to recover for 1 hour or 3 hours (RECOVERY) before processing for two-color immunofluorescent microscopy. TIA-1 protein is identified using a polyclonal antibody (green). Poly(A)+ RNA is revealed by in situ hybridation using an oligo-dT probe (red). Sites of co-localization of TIA-1 and poly(A)+ RNA appear yellow. Nuclei are counterstained using Hoechst dye (blue).

View larger version (37K): [in a new window]   Fig. 2. Translational initiation in the absence or presence of stress. (Green panels) In the absence of stress, eIF2B promotes the charging of the eIF2-GTP-tRNAMet ternary complex by exchanging GDP for GTP. When the eIF2-GTP-tRNAMet ternary complex is available, a canonical 48S preinitiation complex is assembled at the 5' end of capped transcripts (green arrow: Normal) and scanning begins. Upon recognition of the initiation codon by the anticodon of tRNAMet, eIF5 promotes GTP hydrolysis, and early initiation factors are displaced by the 60S ribosomal subunit. As additional ribosomes are added to the transcript, the mRNA is converted into a polysome. (Red panels) In stressed cells (red arrow: Stress), phosphorylation of eIF2 by PKR, PERK, HRI or GCN2 converts eIF2 into a competitive antagonist of eIF2B, depleting the stores of eIF2/GTP/tRNAMet. Under these conditions, TIA-1 is included in a non-canonical, eIF2/eIF5-deficient 48S* preinitiation complex (composed of all components of the 48S pre-initiation complex except eIF2 and eIF5) that is translationally silent. TIA-1 self-aggregation then promotes the accumulation of these complexes at discrete cytoplasmic foci known as stress granules. Blue square, eIF5; green triangle, eIF2 bound to GTP; yellow triangle, eIF2 bound to GDP; red triangle, phospho-eIF2 bound to GDP.

View larger version (26K): [in a new window]   Fig. 3. The dynamic equilibrium between polysomes and stress granules is regulated by the availability of eIF2-GTP-tRNAMet and TIA proteins. Stress-induced activation of eIF2 kinases reduces the concentration of eIF2-GTP-tRNAMet, allowing TIA proteins to promote the assembly of stress granules. Several eukaryotic viruses [e.g. herpes simplex virus (HSV), adenovirus (adeno), vaccinia virus (VV) and influenza virus] prevent stress-induced translational arrest by inhibiting the activity of eIF2 kinases or activating eIF2 phosphatases. Green events and arrows indicate routes leading to translational activation; red events and arrows indicate events leading to translational inhibition.

View larger version (44K): [in a new window]   Fig. 4. Proposed mechanism for the assembly of stress granules. Assembly of an eIF2/eIF5-deficient preinitiation complex at the 5' end of a polysome results in translational arrest (1). As elongating ribosomes `run-off' the mRNA (2,3), the polysome is converted into a 48S* preinitiation complex (4) that is routed by TIA-1 into stress granules (5,6) or productively initiated by the replacement of TIA with eIF5/eIF2/GTP/tRNAmet (green circle). A requirement for HSP 70 and ATP in removing mRNAs from the SG is indicated. Destabilizing elements (red) such as tristetraprolin (TTP) are proposed to direct selected stress granule mRNAs to sites of degradation, whereas stabilizing elements such as HuR (blue) are proposed to direct selected mRNAs to sites of storage and/or reinitiation. By this triage process, the SG may monitor the structure and integrity of mRNP complexes and determine the fate of specific RNAs.