Eukaryotic Initiation Factor 2α-independent Pathway of Stress Granule Induction by the Natural Product Pateamine A

Stress granules are aggregates of small ribosomal subunits, mRNA, and numerous associated RNA-binding proteins that include several translation initiation factors. Stress granule assembly occurs in the cytoplasm of higher eukaryotic cells under a wide variety of stress conditions, including heat shock, UV irradiation, hypoxia, and exposure to arsenite. Thus far, a unifying principle of eukaryotic initiation factor 2α phosphorylation prior to stress granule formation has been observed from the majority of experimental evidence. Pateamine A, a natural product isolated from marine sponge, was recently reported to inhibit eukaryotic translation initiation and induce the formation of stress granules. In this report, the protein composition and fundamental progression of stress granule formation and disassembly induced by pateamine A was found to be similar to that for arsenite. However, pateamine A-induced stress granules were more stable and less prone to disassembly than those formed in the presence of arsenite. Most significantly, pateamine A induced stress granules independent of eukaryotic initiation factor 2α phosphorylation, suggesting an alternative mechanism of formation from that previously described for other cellular stresses. Taking into account the known inhibitory effect of pateamine A on eukaryotic translation initiation, a model is proposed to account for the induction of stress granules by pateamine A as well as other stress conditions through perturbation of any steps prior to the rejoining of the 60S ribosomal subunit during the entire translation initiation process. Stress granules are aggregates of small ribosomal subunits, mRNA, and numerous associated RNA-binding proteins that include several translation initiation factors. Stress granule assembly occurs in the cytoplasm of higher eukaryotic cells under a wide variety of stress conditions, including heat shock, UV irradiation, hypoxia, and exposure to arsenite. Thus far, a unifying principle of eukaryotic initiation factor 2α phosphorylation prior to stress granule formation has been observed from the majority of experimental evidence. Pateamine A, a natural product isolated from marine sponge, was recently reported to inhibit eukaryotic translation initiation and induce the formation of stress granules. In this report, the protein composition and fundamental progression of stress granule formation and disassembly induced by pateamine A was found to be similar to that for arsenite. However, pateamine A-induced stress granules were more stable and less prone to disassembly than those formed in the presence of arsenite. Most significantly, pateamine A induced stress granules independent of eukaryotic initiation factor 2α phosphorylation, suggesting an alternative mechanism of formation from that previously described for other cellular stresses. Taking into account the known inhibitory effect of pateamine A on eukaryotic translation initiation, a model is proposed to account for the induction of stress granules by pateamine A as well as other stress conditions through perturbation of any steps prior to the rejoining of the 60S ribosomal subunit during the entire translation initiation process. Stress granules (SGs) 2The abbreviations used are: SG, stress granule; PatA, pateamine A; B-PatA, biotin-PatA; CHX, cycloheximide; DMDA-PatA, desmethyl, desamino PatA; Me2SO, dimethyl sulfoxide; EMCV, encephalomyocarditis virus; IRES, internal ribosome entry site; PB, processing body; MEF, mouse embryonic fibroblast; eIF, eukaryotic initiation factor; PBS, phosphate-buffered saline; DTT, dithiothreitol; TIA-1, T cell intracellular antigen-1; TIAR, TIA-1 related; SH3, Src homology 3. 2The abbreviations used are: SG, stress granule; PatA, pateamine A; B-PatA, biotin-PatA; CHX, cycloheximide; DMDA-PatA, desmethyl, desamino PatA; Me2SO, dimethyl sulfoxide; EMCV, encephalomyocarditis virus; IRES, internal ribosome entry site; PB, processing body; MEF, mouse embryonic fibroblast; eIF, eukaryotic initiation factor; PBS, phosphate-buffered saline; DTT, dithiothreitol; TIA-1, T cell intracellular antigen-1; TIAR, TIA-1 related; SH3, Src homology 3. were first observed as cellular bodies visible by microscopy in tomato cells subjected to heat shock (1Nover L. Scharf K.D. Neumann D. Mol. Cell. Biol. 1983; 3: 1648-1655Crossref PubMed Scopus (219) Google Scholar, 2Anderson P. Kedersha N. Cell Stress Chaperones. 2002; 7: 213-221Crossref PubMed Scopus (215) Google Scholar, 3Anderson P. Kedersha N. J. Cell Sci. 2002; 115: 3227-3234Crossref PubMed Google Scholar). Subsequently, SGs were identified in mammalian cells exposed to a variety of stress conditions, including oxidative stress, energy depletion, UV irradiation, and hypoxia (4Anderson P. Kedersha N. J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (866) Google Scholar). SG assembly is part of an adaptive response that recruits selected mRNAs and associated proteins for storage or triage to processing bodies (PBs) (5Coller J. Parker R. Annu. Rev. Biochem. 2004; 73: 861-890Crossref PubMed Scopus (394) Google Scholar) that are sites of mRNA decay, allowing survival under adverse conditions. Sequestration of these components may help cells to recover post-stress by replenishing the cellular pool of mRNA without the need for new transcription. The physiological relevance of SGs is underscored by the presence of SGs in tissues of animals under stress (4Anderson P. Kedersha N. J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (866) Google Scholar), and SGs have been implicated in radioresistance of tumor cells (6Moeller B.J. Cao Y. Li C.Y. Dewhirst M.W. Cancer Cell. 2004; 5: 429-441Abstract Full Text Full Text PDF PubMed Scopus (820) Google Scholar) and tumor necrosis factor α signaling (7Kim W.J. Back S.H. Kim V. Ryu I. Jang S.K. Mol. Cell. Biol. 2005; 25: 2450-2462Crossref PubMed Scopus (153) Google Scholar). The study of SGs, their mechanism of formation, and biological role is a relatively new field in cell biology. Thus, a deeper understanding of the mechanism of SG formation and cellular functions may be clinically relevant. A critical step in SG formation shared by most stress conditions is phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2) (8Kedersha N.L. Gupta M. Li W. Miller I. Anderson P. J. Cell Biol. 1999; 147: 1431-1442Crossref PubMed Scopus (894) Google Scholar), which is a component of the eIF2-GTP-tRNAiMet ternary complex. The ternary complex is part of the 43S complex (40S particle, eIF3, and ternary complex) that is recruited to mRNA by the eIF4F complex (eIF4E, eIF4G, and eIF4A) during cap-dependent translation. The tRNAiMet of the ternary complex recognizes the AUG start codon prior to 60S subunit joining and 80S formation. Joining of 60S and release of initiation factors consumes two molecules of GTP, one of which is hydrolyzed by the ternary complex to generate eIF2-GDP (9Merrick W.C. Gene. 2004; 332: 1-11Crossref PubMed Scopus (191) Google Scholar). Phosphorylation of eIF2α increases the affinity of eIF2B (an eIF2 GTP/GDP exchange factor) for eIF2-GDP by ∼150-fold, sequestering the two proteins and inhibiting translation initiation (10Gingras A.C. Raught B. Sonenberg N. Annu. Rev. Biochem. 1999; 68: 913-963Crossref PubMed Scopus (1758) Google Scholar). Ser-51 is the primary site of eIF2α phosphorylation, which can be phosphorylated by several kinases, including the heme-regulated eIF2α kinase, double-stranded RNA-activated protein kinase, the endoplasmic reticulum-localized eIF2α kinase, and GCN2 under different stress conditions (4Anderson P. Kedersha N. J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (866) Google Scholar). The generally accepted model is that phosphorylation of eIF2α is necessary and sufficient for SG assembly (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar), which is supported by several lines of evidence that include: 1) Overexpression of an eIF2α (S51A) mutant blocked SG assembly (12Kedersha N. Chen S. Gilks N. Li W. Miller I.J. Stahl J. Anderson P. Mol. Biol. Cell. 2002; 13: 195-210Crossref PubMed Scopus (440) Google Scholar); 2) Expression of a phosphomimetic eIF2α (S51D) mutant was sufficient to induce SG formation (12Kedersha N. Chen S. Gilks N. Li W. Miller I.J. Stahl J. Anderson P. Mol. Biol. Cell. 2002; 13: 195-210Crossref PubMed Scopus (440) Google Scholar); and 3) eIF2α/S51A knock-in MEFs were not able to assemble SGs upon exposure to arsenite, heat shock, or carbonyl cyanide p-trifluorome-thoxyphenylhydrazone, but eIF2α/S51A mutant cells overexpressing eIF2α/S51D were capable of SG assembly under the same conditions (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 13McInerney G.M. Kedersha N.L. Kaufman R.J. Anderson P. Liljestrom P. Mol. Biol. Cell. 2005; 16: 3753-3763Crossref PubMed Scopus (189) Google Scholar). Aside from eIF2α, several other protein factors have been shown to regulate SG assembly downstream of eIF2α, including T cell intracellular antigen-1 (TIA-1) (14Kedersha N. Cho M.R. Li W. Yacono P.W. Chen S. Gilks N. Golan D.E. Anderson P. J. Cell Biol. 2000; 151: 1257-1268Crossref PubMed Scopus (587) Google Scholar, 15Gilks N. Kedersha N. Ayodele M. Shen L. Stoecklin G. Dember L.M. Anderson P. Mol. Biol. Cell. 2004; 15: 5383-5398Crossref PubMed Scopus (732) Google Scholar) and Ras-GAP-SH3-binding protein (G3BP) (16Tourriere H. Chebli K. Zekri L. Courselaud B. Blanchard J.M. Bertrand E. Tazi J. J. Cell Biol. 2003; 160: 823-831Crossref PubMed Scopus (645) Google Scholar). We and others have recently reported that the marine sponge natural product, pateamine A (PatA), can inhibit translation initiation through interaction with eIF4A (17Bordeleau M.E. Matthews J. Wojnar J.M. Lindqvist L. Novac O. Jankowsky E. Sonenberg N. Northcote P. Teesdale-Spittle P. Pelletier J. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10460-10465Crossref PubMed Scopus (182) Google Scholar, 18Low W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). the of to eIF4A and the of of translation initiation is to the of the eIF4F complex W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). A of desmethyl, desamino by a similar and a that were capable of SGs W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In this have that the cellular bodies observed under are similar to the SGs induced by in of composition and However, SGs independent of eIF2α phosphorylation, in to other stress conditions or arsenite, was to induce the formation of which are sites of mRNA (5Coller J. Parker R. Annu. Rev. Biochem. 2004; 73: 861-890Crossref PubMed Scopus (394) Google Scholar). Cell and DMDA-PatA, and were as previously reported W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, D. K. J.M. L. A. J. Chem. Scopus Google Scholar). arsenite, and were from were from ribosome TIA-1 and eIF2α, and ribosome and ribosomal and for was from TIA-1 and small was as previously reported K. A. M. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar, M. K. A. H. Cell Mol. Biol. 2005; Google Scholar). were by and and which were into the cells and cells were in eIF2α mutant (S51A) and cell lines were as previously reported D. Song B. E. R. P. S. Kaufman R.J. Mol. Cell. 7: Full Text Full Text PDF PubMed Scopus Google Scholar). was to the or as described previously (12Kedersha N. Chen S. Gilks N. Li W. Miller I.J. Stahl J. Anderson P. Mol. Biol. Cell. 2002; 13: 195-210Crossref PubMed Scopus (440) Google Scholar, N. Stoecklin G. Ayodele M. Yacono P. J. Scheuner D. Kaufman R.J. Golan D.E. Anderson P. J. Cell Biol. 2005; PubMed Scopus Google Scholar). cells were on and to recover for In cells were with or small and as for were with for The cells were in PBS, by or and blocked with in prior to of with of primary in different as in the were in of for and in a of and in and for were in for and was and were a 2 and and and or a and a and and were or from the are shown the are shown and from the are shown in SGs are and is into cells were with as and with A, cells were with or for by with by The cells were in in the presence or of for 2 and were with for by with arsenite, DMDA-PatA, or for cells were with for and with TIA-1 or stress granules with similar composition as those induced by but not induce processing A, cells were exposed to for or for and and with cells for and cells for ribosomal protein and ribosomal protein cells for eIF4A and of the are shown as and as a the of were as in A and and as and TIA-1 and of the and are shown the of The the of which are not by and not in induced by in TIA-1 and were with or for were and for the SG protein In and or encephalomyocarditis internal ribosome entry sites O. Pelletier J. 2004; PubMed Scopus Google Scholar) were by and was the of was in of of and 2 DTT, and of with the of arsenite. were for A was for to the of the of was with of of and of and 2 in a of The were for with of and and that were subjected to in a for were from the of the and the of in was by mutant and cells were as for were with and in of 2 DTT, and in the were and 2 for 2 was in a were from the of the by of from the of the SGs by and in a of protein components of SGs have been identified P. Kedersha N. Cell Stress Chaperones. 2002; 7: 213-221Crossref PubMed Scopus (215) Google Scholar, 3Anderson P. Kedersha N. J. Cell Sci. 2002; 115: 3227-3234Crossref PubMed Google Scholar, P. Kedersha N. J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (866) Google Scholar, N. Chen S. Gilks N. Li W. Miller I.J. Stahl J. Anderson P. Mol. Biol. Cell. 2002; 13: 195-210Crossref PubMed Scopus (440) Google Scholar). that the cellular bodies formed by are SGs, cells were with the SG or with and for a of SG proteins SG protein protein small ribosomal subunit protein and were to SGs upon of cells with or arsenite. SGs induced by not the ribosome subunit protein and and or and that and induce SGs of similar in to SGs, cells were with and with cells with arsenite, which has been shown to induce SGs and which are N. Stoecklin G. Ayodele M. Yacono P. J. Scheuner D. Kaufman R.J. Golan D.E. Anderson P. J. Cell Biol. 2005; PubMed Scopus Google Scholar). SGs were or TIA-1 SGs and were their protein independent the protein and were used to formation. induced SG and formation a in which in the of which are by in the However, a to that induced formation, in to induce SG SG and of formation of SGs is and SGs are upon of stress conditions, with components including mRNA SGs, and other granules as (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, N. Stoecklin G. Ayodele M. Yacono P. J. Scheuner D. Kaufman R.J. Golan D.E. Anderson P. J. Cell Biol. 2005; PubMed Scopus Google Scholar). cells were with arsenite, PatA, or DMDA-PatA, SGs were observed cells that were with and to recover in SGs were in cells but visible in and cells and by inhibiting and inhibit SG assembly (14Kedersha N. Cho M.R. Li W. Yacono P.W. Chen S. Gilks N. Golan D.E. Anderson P. J. Cell Biol. 2000; 151: 1257-1268Crossref PubMed Scopus (587) Google Scholar). allowing cells to recover in the presence of CHX, SGs were in cells with or DMDA-PatA, similar to and of cells with for blocked SG formation in response to by We have previously shown that to the formation of the complex and W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). and into SGs under is into The of a W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) for of to was able to induce SGs similar to DMDA-PatA, as by of the SG TIA-1, and was SGs as by with TIA-1 these that formation of SGs is and that is into eIF2α Phosphorylation for phosphorylation of eIF2α Ser-51 has been shown to a critical role in the of protein and induction of SG formation by (4Anderson P. Kedersha N. J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (866) Google Scholar). The phosphorylation of eIF2α was by of from cells with DMDA-PatA, arsenite, or induced the phosphorylation of eIF2α as previously reported (12Kedersha N. Chen S. Gilks N. Li W. Miller I.J. Stahl J. Anderson P. Mol. Biol. Cell. 2002; 13: 195-210Crossref PubMed Scopus (440) Google Scholar). In not induce phosphorylation of eIF2α in with The of a of eIF2α has been to inhibit SG formation induced by (8Kedersha N.L. Gupta M. Li W. Miller I. Anderson P. J. Cell Biol. 1999; 147: 1431-1442Crossref PubMed Scopus (894) Google Scholar), and SG assembly not MEFs that a knock-in in the eIF2α are exposed to (8Kedersha N.L. Gupta M. Li W. Miller I. Anderson P. J. Cell Biol. 1999; 147: 1431-1442Crossref PubMed Scopus (894) Google Scholar, E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). was found that of the eIF2α mutant effect on SG formation in the presence of DMDA-PatA, SG formation by the of SG formation from eIF2α phosphorylation, SG induction in eIF2α/S51A mutant and of cells with or in the formation of SGs or In the eIF2α/S51A mutant was to induce SG formation as previously described (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). However, induced the formation of SGs in the eIF2α/S51A mutant MEFs similar to and was that in SGs not eIF2α, eIF2α was to SGs induced by in and eIF2α/S51A mutant cells that SG formation induced by is independent of eIF2α of and downstream of to SG assembly through (8Kedersha N.L. Gupta M. Li W. Miller I. Anderson P. J. Cell Biol. 1999; 147: 1431-1442Crossref PubMed Scopus (894) Google Scholar). protein was with small in was effect on SG assembly induced by or the two were observed in TIA-1 or MEFs of TIA-1 or not SG formation, to of by the other are the of SGs, the and of SGs on the and of the proteins known to SG TIA-1, TIAR, and (4Anderson P. Kedersha N. J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (866) Google Scholar). However, TIA-1 MEFs a SG response to and by assembly of SGs, MEFs SGs in response to We previously reported that SGs are in TIA-1 MEFs SG assembly N. Kedersha N. Ayodele M. Shen L. Stoecklin G. Dember L.M. Anderson P. Mol. Biol. Cell. 2004; 15: 5383-5398Crossref PubMed Scopus (732) Google Scholar) similar to those observed for In of by from translation and SGs in (8Kedersha N.L. Gupta M. Li W. Miller I. Anderson P. J. Cell Biol. 1999; 147: 1431-1442Crossref PubMed Scopus (894) Google Scholar), the effect of on translation initiation in and the first was by cap-dependent initiation and the was by the or the O. Pelletier J. 2004; PubMed Scopus Google Scholar). shown in cap-dependent translation and translation from were by arsenite. of translation initiation with W.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar) that a of as with of 80S to were with not the However, with the of the 80S and an a similar to in effect of is similar to that for W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). However, the of and translation initiation from PatA, which W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In have been in and in (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). and the of and the of a the as previously eIF2α/S51A mutant a perturbation of the However, In of and the of the in the eIF2α/S51A mutant The of to the of eIF2α/S51A mutant MEFs and the for eIF2α/S51A mutant and MEFs for the that eIF2α phosphorylation is for SG induction by arsenite, but not by In this the natural product and and B-PatA, which were recently shown to induce SGs W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), as to the mechanism of SG SGs through of heme-regulated eIF2α kinase, which eIF2α Ser-51 (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). as a have that the induction of SGs by is not on the phosphorylation of the reported SG formation has not been with eIF2α phosphorylation energy induced by with the carbonyl cyanide in cells (12Kedersha N. Chen S. Gilks N. Li W. Miller I.J. Stahl J. Anderson P. Mol. Biol. Cell. 2002; 13: 195-210Crossref PubMed Scopus (440) Google Scholar), or with the (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). However, of these SGs in eIF2α/S51A mutant suggesting that a of eIF2α phosphorylation is (11McEwen E. Kedersha N. Song B. Scheuner D. Gilks N. Han A. Chen J.J. Anderson P. Kaufman R.J. J. Biol. Chem. 2005; 280: 16925-16933Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). that eIF2α phosphorylation was an to SG formation (4Anderson P. Kedersha N. J. Cell Biol. 2006; 172: 803-808Crossref PubMed Scopus (866) Google Scholar). an SG assembly is not on eIF2α phosphorylation, new on the mechanism of SG formation. The that the majority of to have implicated the phosphorylation of eIF2α as a necessary step for SG formation the of the granules induced by and are and a of eIF2 SGs, and of induction for The of cells to recover from or by of cells and in that SGs induced by are more stable than those induced by arsenite. However, the of components and the of SGs induced by PatA, with a of disassembly than that observed for SGs, that SGs formed in the presence of are similar to SGs described for other stresses. the to and of the MEFs to and that SGs are The of eIF2 from SGs for and in SGs for is with SGs on eIF2α arsenite, phosphorylation of eIF2α the of the ternary inhibiting translation initiation (8Kedersha N.L. Gupta M. Li W. Miller I. Anderson P. J. Cell Biol. 1999; 147: 1431-1442Crossref PubMed Scopus (894) Google Scholar). SGs are aggregates of initiation the of ternary complex formation eIF2 from the initiation their from However, of eIF2α into SGs that ternary are are part of the 43S and into The in formation may be to the mechanism of SG assembly and may be as and heat shock not induce N. Stoecklin G. Ayodele M. Yacono P. J. Scheuner D. Kaufman R.J. Golan D.E. Anderson P. J. Cell Biol. 2005; PubMed Scopus Google Scholar). Thus, SGs are similar in composition to SGs induced by arsenite, their of formation In translation initiation by eIF4F However, a in the reported experimental evidence. In one study (17Bordeleau M.E. Matthews J. Wojnar J.M. Lindqvist L. Novac O. Jankowsky E. Sonenberg N. Northcote P. Teesdale-Spittle P. Pelletier J. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10460-10465Crossref PubMed Scopus (182) Google Scholar), the formation of by the of 43S with In W.K. Y. W.C. D. Mol. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), not 43S joining to but the of the complex with 80S formation. of into SGs, through eIF4A may account for the of and the to recover cells by with The presence of SGs in and are into SG assembly to in two the initiation to of and the of these into SGs that through an process. have previously proposed an that selected mRNA for under N. Stoecklin G. Ayodele M. Yacono P. J. Scheuner D. Kaufman R.J. Golan D.E. Anderson P. J. Cell Biol. 2005; PubMed Scopus Google Scholar). The of induction by may that this is blocked or not induced for SGs formed in the presence of Thus, the of SG eIF2α phosphorylation and the downstream for and arsenite, but the for SGs The of the ternary complex to the ribosomal subunit is not the site of which the eIF4F complex. has several cellular as protein Chem. Biol. PubMed Scopus Google Scholar), of the 2004; PubMed Scopus Google Scholar), oxidative stress, and of several signaling Rev. 2002; PubMed Scopus Google Scholar, M. Li A. B. K. M. J. 15: PubMed Scopus Google Scholar, L. J. J. Rev. 2000; 3: PubMed Scopus Google Scholar), with downstream heme-regulated eIF2α to eIF2α is not that is able to induce SG formation without that any factor or that and associated from a 80S can induce The that a that 60S to the SGs M. J.M. J. S. Mol. Biol. Cell. 2005; 16: PubMed Scopus Google Scholar) this SGs may be a product of a that to the of this process. the translation associated with SGs the is of In to proteins in protein translation and SGs have been shown to proteins in cellular cells into SGs through interaction with eIF4G, which the signaling from tumor necrosis factor α to (7Kim W.J. Back S.H. Kim V. Ryu I. Jang S.K. Mol. Cell. Biol. 2005; 25: 2450-2462Crossref PubMed Scopus (153) Google Scholar). The protein an component of is associated with SGs under stress conditions I. M. M. H. Mol. Biol. Cell. 2006; PubMed Scopus Google Scholar). of the have different of SGs during and this with of translation initiation 2005; PubMed Scopus Google Scholar). that SGs may and in different physiological or stresses. The of to inhibit protein translation and SG formation, which to the induction of has been for the of for Chen Li J. W. Chen Y. L. J. P. Chen Chen PubMed Google Scholar). The that SGs the of small natural as to study biological and be for the study of cellular stress, may We and for of and to We and for and We for with of the We an for the more by the of of with