RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules.
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.
Kedersha
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Division of Rheumatology and Immunology, Brigham and Women's Hospital, Smith Building, Boston, Massachusetts 02115, USA.
Gupta
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Li
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Miller
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Anderson
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D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000074019:T-Cell Intracellular Antigen-1; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D015852:Eukaryotic Initiation Factor-2; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C076751:TIAL1 protein, human