TRB3 Inhibits the Transcriptional Activation of Stress-regulated Genes by a Negative Feedback on the ATF4 Pathway

Abstract

The integrated stress response (ISR) is defined as a highly conserved response to several stresses that converge to the induction of the activating transcription factor 4 (ATF4). Because an uncontrolled response may have deleterious effects, cells have elaborated several negative feedback loops that attenuate the ISR. In the present study, we describe how induction of the human homolog of Drosophila tribbles (TRB3) attenuates the ISR by a negative feedback mechanism. To investigate the role of TRB3 in the control of the ISR, we used the regulation of gene expression by amino acid limitation as a model. The enhanced production of ATF4 upon amino acid starvation results in the induction of a large number of target genes like CHOP (CAAT/enhancer-binding protein-homologous protein), asparagine synthetase (ASNS), or TRB3. We demonstrate that TRB3 overexpression inhibits the transcriptional induction of CHOP and ASNS whereas TRB3 silencing induces the expression of these genes both under normal and stressed conditions. In addition, transcriptional profiling experiments show that TRB3 affects the expression of many ISR-regulated genes. Our results also suggest that TRB3 and ATF4 belong to the same protein complex bound to the sequence involved in the ATF4-dependent regulation of gene expression by amino acid limitation. Collectively, our data identify TRB3 as a negative feedback regulator of the ATF4-dependent transcription and participates to the fine regulation of the ISR. The integrated stress response (ISR) is defined as a highly conserved response to several stresses that converge to the induction of the activating transcription factor 4 (ATF4). Because an uncontrolled response may have deleterious effects, cells have elaborated several negative feedback loops that attenuate the ISR. In the present study, we describe how induction of the human homolog of Drosophila tribbles (TRB3) attenuates the ISR by a negative feedback mechanism. To investigate the role of TRB3 in the control of the ISR, we used the regulation of gene expression by amino acid limitation as a model. The enhanced production of ATF4 upon amino acid starvation results in the induction of a large number of target genes like CHOP (CAAT/enhancer-binding protein-homologous protein), asparagine synthetase (ASNS), or TRB3. We demonstrate that TRB3 overexpression inhibits the transcriptional induction of CHOP and ASNS whereas TRB3 silencing induces the expression of these genes both under normal and stressed conditions. In addition, transcriptional profiling experiments show that TRB3 affects the expression of many ISR-regulated genes. Our results also suggest that TRB3 and ATF4 belong to the same protein complex bound to the sequence involved in the ATF4-dependent regulation of gene expression by amino acid limitation. Collectively, our data identify TRB3 as a negative feedback regulator of the ATF4-dependent transcription and participates to the fine regulation of the ISR. Cells have evolved specific signaling pathways to ensure adaptation to stress. For example, the integrated stress response (ISR), 3The abbreviations used are: ISR, integrated stress response; AARE, amino acid response element; ASNS, asparagine synthetase; ATF, activating transcription factor; CHOP, C/EBP homologous protein; MEF, mouse embryonic fibroblast; qRT-PCR, quantitative reverse transcriptase-PCR; NSRE, nutrient sensing response element; DMEM, Dulbecco's modified Eagle's medium; ChIP, chromatin immunoprecipitation assay; PBS, phosphate-buffered saline; PMSF, phenylmethylsulfonyl fluoride; ER, endoplasmic reticulum; DTT, dithiothreitol. which is highly conserved from yeast to mammals, integrates signaling from multiple stress pathways. The ISR acts downstream of the eukaryotic translation initiation factor 2 (eIF2α) phosphorylation (1Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2384) Google Scholar, 2Harding H.P. Calfon M. Urano F. Novoa I. Ron D. Annu. Rev. Cell Dev. Biol. 2002; 18: 575-599Crossref PubMed Scopus (809) Google Scholar, 3Dever T.E. Cell. 2002; 108: 545-556Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar, 4Rutkowski D.T. Kaufman R.J. Dev. Cell. 2003; 4: 442-444Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). In mammals, distinct stress signals activate four eIF2α kinases: PKR (activated by double-stranded RNA during viral infection (5Kaufman R.J. Sonenberg N. Mathews M.B. Translational Control of Gene Expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000: 503-527Google Scholar)), GCN2 (activated by uncharged tRNAs, adapts cells to amino acid starvation (6Harding H.P. Novoa I.I. Zhang Y. Zeng H. Wek R. Schapira M. Ron D. Mol. Cell. 2000; 6: 1099-1108Abstract Full Text Full Text PDF PubMed Google Scholar, 7Zhang P. 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This transcription factor plays a crucial role for the adaptation to stresses by regulating the expression of many genes. As shown by Harding et al. (1Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2384) Google Scholar), ATF4 controls many genes involved in metabolism and transport of amino acid and in resistance to oxidative stress. In addition, several ATF4 target genes, such as CHOP, are themselves transcription factors that regulate the expression of a set of stress-induced target genes and amplify the signal initiated by the original stress (10Sok J. Wang X.Z. Batchvarova N. Kuroda M. Harding H. Ron D. Mol. Cell. Biol. 1999; 19: 495-504Crossref PubMed Google Scholar, 11Wang X.Z. Kuroda M. Sok J. Batchvarova N. Kimmel R. Chung P. Zinszner H. Ron D. EMBO J. 1998; 17: 3619-3630Crossref PubMed Scopus (271) Google Scholar, 12Zinszner H. Kuroda M. Wang X. Batchvarova N. Lightfoot R.T. Remotti H. Stevens J.L. Ron D. Genes Dev. 1998; 12: 982-995Crossref PubMed Google Scholar). Because an uncontrolled response to stress may have deleterious effects, cells have elaborated a negative feedback loop that attenuates the ISR. Indeed, in response to stresses, the induction of GADD34 mediates eIF2α dephosphorylation and allows protein synthesis to recover to translate the product of induced genes (13Novoa I. Zeng H. Harding H.P. Ron D. J. Cell Biol. 2001; 153: 1011-1022Crossref PubMed Scopus (1040) Google Scholar, 14Novoa I. Zhang Y. Zeng H. Jungreis R. Harding H.P. Ron D. EMBO J. 2003; 22: 1180-1187Crossref PubMed Scopus (350) Google Scholar). These observations indicate that GADD34 controls a programmed shift from translational repression to stress-induced gene expression and reconciles the apparent contradiction between the translational and transcriptional arms of cellular stress responses. In a context of amino acid starvation, it shown that the expression of many genes is induced the For genes and a involved in the transcriptional by starvation and acid response C. Wang X.Z. Ron D. M. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google and response F. Chen C. C. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). data from our J. C. G. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google and F. R. Chen H. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, C. Chen C. J. 2003; PubMed Scopus Google have shown that these are to the mRNA that are induced by amino acid the induction for the of Drosophila also as or that protein a for a number of signaling pathways. TRB3 as a protein for and et al. M. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google that TRB3 is involved in a negative feedback control of gene expression the set of that TRB3 ATF4 and inhibits the transcriptional of ATF4 D. T. Cell 2003; PubMed Scopus Google Scholar, D. T. PubMed Scopus Google Scholar). In addition, a the role of TRB3 under by that cellular stresses both and TRB3 expression X. C. Y. Biol. 4: PubMed Google Scholar). The of TRB3 induction during stress by et al. N. S. T. H. EMBO J. PubMed Scopus Google that TRB3 is involved in the of programmed during ER stress. of on TRB3 from that that TRB3 is involved in the control of both and S. M. 2003; PubMed Scopus Google Scholar, L. R. N. S. J. C. M. J. M. PubMed Scopus Google Scholar). Indeed, show TRB3 inhibits is during S.H. H. S. S. R. J. M. PubMed Scopus Google Scholar), an expression of TRB3 in to in these that TRB3 as a in the of metabolism S. M. 2003; PubMed Scopus Google Scholar). the same that TRB3 by the of in and that TRB3 in from L. R. N. S. J. C. M. J. M. PubMed Scopus Google Scholar). data demonstrate that TRB3 is by many and is involved in the fine control of several signaling pathways. In the context of amino acid regulation of gene we the role of TRB3 in the regulation of the ISR. We demonstrate that TRB3 is a negative feedback regulator of transcription and participates to the fine regulation of the amino acid response and of the ISR. Cell and cells in Dulbecco's modified Eagle's cells in of and cells in of used for In experiments amino acid starvation, embryonic in ATF4 by D. Ron (1Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2384) Google Scholar). and in and by the as C. Wang X.Z. Ron D. M. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). of the cells of a the gene to the human as an Cells to the for in phosphate-buffered and cells amino for Cells and and as F. J. Mol. Google Scholar). as the of and as J. C. P. J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). by the sequence of TRB3 in the and of the and by ATF4 sequence amino and amino the sequence in the of Gene RNA as P. N. PubMed Scopus Google and to RNA by RNA of to the for mouse in CHOP reverse ASNS reverse TRB3 reverse and for human in cells and CHOP reverse ASNS reverse TRB3 reverse used and of in To control for RNA and mRNA also reverse reverse quantitative a as J. C. G. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). results as of CHOP, ASNS, or TRB3 ATF4 from used for and The TRB3 from the from and the from The used for immunoprecipitation that and and that and from for the of mouse and TRB3 as Cells for 4 in PMSF, from in of DTT, PMSF, from 4 in DTT, PMSF, from for the of human TRB3 by for on in PMSF, from of by and a by in in PBS, for The in 4 to the The in and the from Cell in for in the the enhanced to the of Y. L. C. N. C. P. Google Scholar). Cells and for Cells to to either or for the in by to the to a of and by the of to a of chromatin a for of 2 on between from cells or of The complex by protein The in the complex by the and a and quantitative by a and a the of the The to a of or used the human CHOP AARE, and mouse CHOP and mouse CHOP and mouse CHOP and mouse ASNS NSRE, and human ASNS NSRE, and The for to activate the by for for and for for by in the from to to ensure that a product in the The results are as the to are the from chromatin and the immunoprecipitation as in the The for in and the used for a and to human TRB3 mRNA and control and used as a negative experiments as J. C. G. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Cells in and 2 of and of the cells are in either or for 4 or either for or for of gene expression qRT-PCR, as RNA from either cells or or cells and to the from and human from The an on the to the Gene expression and the and We used a a of and a of to identify genes by starvation in and TRB3 the role of the we genes induced by amino acid In our TRB3 as the induced amino acid starvation To the regulation of TRB3 by amino acid starvation, we the of TRB3 expression in response to mouse embryonic in either or for and the protein of TRB3 by TRB3 in control cells induced a starvation for TRB3 induction by amino acid starvation is to cells to starvation it in and for amino limitation The expression of TRB3 protein that of the that TRB3 is downstream of To investigate the of TRB3 the TRB3 mRNA by quantitative starvation, in or TRB3 mRNA as as starvation in cells and a 2 In the of TRB3 mRNA induction Because TRB3 induction amino acid starvation to we stress to also to TRB3. For that or for 4 a an ER stress. also strongly induced TRB3 mRNA in cells whereas induction in cells of TRB3 CHOP and ASNS by et al. D. T. Cell 2003; PubMed Scopus Google have shown that TRB3 ATF4 and inhibits ATF4 transcriptional by gene To investigate the role of TRB3 on the regulation of gene expression by amino acid starvation, a cells the a an of human TRB3 a the and a by a of the human and 2 The and or for and in either control or for 4 that a strongly a in the or of in the whereas protein in the Because the protein synthesis we that for ATF4 expression in both and an specific for human we that the of overexpression upon induction and the TRB3 amino acid starvation the same This that the of TRB3 induction are and To TRB3 the induction of genes to induced by amino acid starvation in a we by quantitative CHOP and ASNS mRNA in In the in cells or for and in either control or for We that CHOP mRNA induced to starvation in whereas in cells the induction by starvation strongly The results for ASNS induction by starvation by TRB3 This in TRB3 between CHOP and ASNS by the of that may regulate CHOP expression in response to starvation mRNA C. Wang X.Z. Ron D. M. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Because the ISR in response to we the of TRB3 on ASNS expression in cells to an ER stress. that ASNS induction by TRB3 In we CHOP expression in to the ATF4 ER stress signaling regulating CHOP transcription stress have in the CHOP the results to the results in and show that TRB3 overexpression inhibits the mRNA of CHOP and ASNS in response to amino acid starvation or ER stress. To investigate the of TRB3 acts by regulating the we the regulation of a gene by a by 2 of either or of These or cells and the expression in response to starvation in the or of As starvation strongly induced both and 2 transcriptional in In TRB3 induced by to induction These data show that of CHOP and ASNS expression is the of the of the of TRB3 ATF4 Gene by the that a of TRB3 by to an of ATF4 target genes expression upon we the of the TRB3 by and in control and cells either TRB3 or Control in either control or for and that TRB3 strongly induced by starvation in cells by Control whereas both and induced of TRB3 strongly in cells TRB3 In the same we ASNS mRNA and that both and induced of ASNS 4 and 2 cells TRB3 control We the of TRB3 on the response to starvation the and These cells and in control and For both the and the induced enhanced cells TRB3 control these results show that TRB3 is induced by the ISR and the TRB3 is a negative feedback regulator of the TRB3 ATF4 in the to the for of the is several for the of TRB3 upon of TRB3 to ATF4 or This is the of the Drosophila TRB3 which shown to the and of the a C/EBP transcription factor involved in during P. G. Mol. Cell. 2000; 6: Full Text Full Text PDF PubMed Scopus Google Scholar). in mammals, TRB3 to a role in protein Indeed, TRB3 shown to CHOP and ATF4 D. T. Cell 2003; PubMed Scopus Google Scholar, N. S. T. H. EMBO J. PubMed Scopus Google Scholar). Our results these observations the of TRB3 in cells the of ATF4 Our that TRB3 ATF4 to the Indeed, starvation ATF4 which to the in transcription to regulate target genes J. C. G. P. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). To ATF4 is by TRB3 cells or for and in either control or for 2 we that TRB3 ATF4 on both CHOP and ASNS Because TRB3 ATF4 on we that TRB3 ATF4 on To cells for 4 in either control or cells and and either the the or the of the CHOP gene The results show a in both ATF4 and TRB3 to the of ATF4 and TRB3 on the and in the of CHOP and induced by these results suggest that ATF4 and TRB3 the CHOP gene on the to that ATF4 and TRB3 belong to the same protein complex that the AARE, we of chromatin both immunoprecipitation the a immunoprecipitation the control experiments or as that both the CHOP and the ASNS are from the and used in the These results suggest that TRB3 and ATF4 are present in the same protein complex that to the TRB3 ATF4-dependent of TRB3 inhibits transcription by to the ATF4 protein complex bound on the involved in it affects chromatin regulation of or it the between ATF4 and the transcription Chen et al. H. J. Biol. Full Text Full Text PDF PubMed Scopus Google a in ASNS during amino acid in and we the of TRB3 overexpression on and that and on ASNS starvation by TRB3 overexpression data CHOP of to involved in the of ASNS transcription upon amino acid This is the that is also on We that TRB3 the between ATF4 and of specific or Indeed, ATF4 shown to such as to the transcription initiation complex such as G. T. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, ATF4 is a transcription factor to as a a specific transcription which to the To specific of ATF4 are involved during amino acid starvation, we the of TRB3 on ATF4-dependent transcription in an context specific For that we used a in which ATF4 and factors are present and in which factor ATF4 in the context of amino acid starvation are a protein of the yeast and the transcriptional of ATF4 a the gene under the control of we the expression of by in or of TRB3. Because it shown that TRB3 ATF4 between the amino and we have control The the to a of ATF4 that a transcriptional TRB3. The the of ATF4 that TRB3 and of the to and G. T. J. Biol. Full Text Full Text PDF PubMed Scopus Google ATF4 several transcriptional protein to activate As that of ATF4 to in transcriptional of the gene as we that the overexpression of TRB3 strongly the by the and whereas it on the that TRB3 These results demonstrate that of TRB3 to ATF4 inhibits ATF4 of specific We that specific transcription factor of ATF4 as as the chromatin context is involved in the TRB3 it is that TRB3 affects the ATF4-dependent transcription by the of or by to TRB3 the of Genes upon the of the shown that the ISR controls the expression of many genes involved in amino acid metabolism and resistance to oxidative stress in (1Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2384) Google Scholar). gene expression we the of TRB3 on ATF4-dependent genes. In our study, we used a a of and a of to identify genes by starvation, and we both ATF4 and the of TRB3 overexpression on amino of we that by regulate gene expression by the of genes in cells and for genes to by and genes the of the of TRB3 We also TRB3 overexpression by affects the expression of genes by the of genes in cells and for We that TRB3 overexpression induces genes the genes by starvation, of to by TRB3 overexpression To the ATF4 and the of TRB3 we data from and cells to data from cells or by Because it to TRB3 is by human cells and ATF4 by we the to genes induced by starvation in both We genes induced by a starvation in both these genes, are ATF4-dependent genes in and genes are or in or In to TRB3 effects, we that a gene is by TRB3 overexpression of induction upon starvation is in cells TRB3. genes are by TRB3 overexpression in whereas the induction of genes is in of genes induced by amino acid starvation in both and ATF4 cells in a we on the ATF4-dependent genes, we that of the ATF4-dependent genes are by TRB3 and of the genes by TRB3 are ATF4-dependent genes. the the genes are by TRB3. is that the of TRB3 the induction of genes by starvation may ATF4-dependent the of TRB3 expression to We that TRB3 plays a role in a large of the ATF4-dependent genes. In we show that TRB3 inhibits a the ISR. Indeed, TRB3 is induced by ISR stress or amino acid an ATF4-dependent TRB3 overexpression strongly inhibits the ATF4-dependent the our results suggest that TRB3 to the ATF4 complex bound on target and inhibits In the context of genes by amino acid starvation, transcriptional profiling that TRB3 genes. Our results also demonstrate that TRB3 is involved in the control of the of gene expression under conditions. Indeed, in whereas TRB3 is a by the of ASNS in the of CHOP expression also on the of these genes, our results demonstrate that TRB3 controls the expression of genes by ATF4 under both stressed and conditions. Because ATF4 is in many such as T. D. 1998; PubMed Scopus Google Scholar), 2002; PubMed Scopus Google Scholar, T. Leiden J.M. Dev. Biol. 2000; PubMed Scopus Google amino acid and resistance to oxidative stress (1Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2384) Google we that TRB3 also participates to the fine regulation of these Although TRB3 is conserved in many the involved in the regulation of gene expression to between and In tribbles shown to specific protein P. G. Mol. Cell. 2000; 6: Full Text Full Text PDF PubMed Scopus Google Scholar). in mammals, TRB3 to a role in protein Indeed, data D. T. Cell 2003; PubMed Scopus Google Scholar, N. S. T. H. EMBO J. PubMed Scopus Google and our results indicate that ATF4 for the of TRB3 on ATF4 our data suggest that TRB3 inhibits ATF4 by on the is that TRB3 inhibits ATF4 by the of to such as and G. T. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). from TRB3 as a for a number of signaling pathways Cell 19: PubMed Scopus Google Scholar). This is by the transcriptional profiling which demonstrate that overexpression of TRB3 regulate gene of the of TRB3 the control of et al. N. S. T. H. EMBO J. PubMed Scopus Google have shown that TRB3 is involved in the control of during ER stress. ATF4 and CHOP have shown to of and Because TRB3 have shown to regulate these it is to that TRB3 may a between these cellular under stress conditions. Our that TRB3 inhibits the ISR a feedback the that TRB3 a for ER stress-induced in of a of the ISR, the induced TRB3 the expression of ATF4-dependent genes. the role of TRB3 complex et al. N. S. T. H. EMBO J. PubMed Scopus Google that TRB3 overexpression in response to of in of ER TRB3 by a from the of ATF4-dependent Because ER stress signaling pathways and is by the of several the of the role of TRB3 in the control of to a the for TRB3. that TRB3 inhibits by in S. M. 2003; PubMed Scopus Google and inhibits in L. R. N. S. J. C. M. J. M. PubMed Scopus Google Scholar), a role of TRB3 in and observations TRB3 expression shown to strongly in the of or resistance and a in the TRB3 gene is resistance and in S. F. S. S. M. R. G. B. PubMed Scopus Google Scholar). The involved in the regulation of TRB3 expression in and have Because TRB3 is involved in the regulation of many in several it is that many regulate We ATF4 the plays a role in the control of TRB3 expression in data that TRB3 is involved in the control of amino acid and protein et al. R. N. Y. J. Biol. Full Text Full Text PDF PubMed Scopus Google have shown that TRB3 is a regulator of by our results that TRB3 inhibits ATF4 in response to amino acid starvation that TRB3 involved in the control of amino acid Indeed, that ATF4 is in the control of amino acid metabolism and transport (1Harding H.P. Zhang Y. Zeng H. Novoa I. Lu P.D. Calfon M. Sadri N. Yun C. Popko B. Paules R. Stojdl D.F. Bell J.C. Hettmann T. Leiden J.M. Ron D. Mol. Cell. 2003; 11: 619-633Abstract Full Text Full Text PDF PubMed Scopus (2384) Google Scholar), we that TRB3 also involved in In addition, we have shown that the GCN2 controls the amino acid in C. J. L. Y. Zeng H. Zhang Y. Harding H.P. Ron D. P. Cell Full Text Full Text PDF PubMed Scopus Google Scholar). Because ATF4 is the downstream of GCN2 it is to that ATF4 and TRB3 also to the control of amino acid these observations we that TRB3 may a regulator of the role of TRB3 in the control of the amino acid a to is that the of the integrated stress response a highly of to a fine regulation of transcriptional Our results show that TRB3 the ISR by a negative feedback mechanism. the TRB3 is involved under stressed and normal in the fine control of genes. demonstrate that TRB3 is an factor in the response to nutrient starvation, the and the regulation of cellular such as the role of TRB3 and the regulation of expression our on the control of several signaling pathways. TRB3 may a target for or that We for the of data and and for