Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation.
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.
Anderson
Paul
P
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA. panderson@rics.bwh.harvard.edu
Kedersha
Nancy
N
D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D039102:Poly(A)-Binding Proteins; D011132:Polyribosomes / Q000502:physiology; D014176:Protein Biosynthesis / Q000502:physiology*; D011506:Proteins; D012326:RNA Splicing / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology*; D000074019:T-Cell Intracellular Antigen-1; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D014409:Tumor Necrosis Factor-alpha; C076751:TIAL1 protein, human