An Upstream Open Reading Frame Regulates Translation of GADD34 during Cellular Stresses That Induce eIF2α Phosphorylation

Cellular stress such as endoplasmic reticulum stress, hypoxia, and viral infection activates an integrated stress response, which includes the phosphorylation of the eukaryotic initiation factor 2α (eIF2α) to inhibit overall protein synthesis. Paradoxically, this leads to translation of a subset of mRNAs, like transcription factor ATF4, which in turn induces transcription of downstream stress-induced genes such as growth arrest DNA-inducible gene 34 (GADD34). GADD34 interacts with protein phosphatase 1 to dephosphorylate eIF2α, resulting in a negative feedback loop to recover protein synthesis and allow translation of stress-induced transcripts. Here, we show that GADD34 is not only transcriptionally induced but also translationally regulated to ensure maximal expression during eIF2α phosphorylation. GADD34 mRNAs are preferentially associated with polysomes during eIF2α phosphorylation, which is mediated by its 5′-untranslated region (5′UTR). The human GADD34 5′UTR contains two non-overlapping upstream open reading frames (uORFs), whereas the mouse version contains two overlapping and out of frame uORFs. Using 5′UTR GADD34 reporter constructs, we show that the downstream uORF mediates repression of basal translation and directs translation during eIF2α phosphorylation. Furthermore, we show that the upstream uORF is poorly translated and that a proportion of scanning ribosomes bypasses the upstream uORF to recognize the downstream uORF. These findings suggest that GADD34 translation is regulated by a unique 5′UTR uORF mechanism to ensure proper GADD34 expression during eIF2α phosphorylation. This mechanism may serve as a model for understanding how other 5′UTR uORF-containing mRNAs are regulated during cellular stress. Cellular stress such as endoplasmic reticulum stress, hypoxia, and viral infection activates an integrated stress response, which includes the phosphorylation of the eukaryotic initiation factor 2α (eIF2α) to inhibit overall protein synthesis. Paradoxically, this leads to translation of a subset of mRNAs, like transcription factor ATF4, which in turn induces transcription of downstream stress-induced genes such as growth arrest DNA-inducible gene 34 (GADD34). GADD34 interacts with protein phosphatase 1 to dephosphorylate eIF2α, resulting in a negative feedback loop to recover protein synthesis and allow translation of stress-induced transcripts. Here, we show that GADD34 is not only transcriptionally induced but also translationally regulated to ensure maximal expression during eIF2α phosphorylation. GADD34 mRNAs are preferentially associated with polysomes during eIF2α phosphorylation, which is mediated by its 5′-untranslated region (5′UTR). The human GADD34 5′UTR contains two non-overlapping upstream open reading frames (uORFs), whereas the mouse version contains two overlapping and out of frame uORFs. Using 5′UTR GADD34 reporter constructs, we show that the downstream uORF mediates repression of basal translation and directs translation during eIF2α phosphorylation. Furthermore, we show that the upstream uORF is poorly translated and that a proportion of scanning ribosomes bypasses the upstream uORF to recognize the downstream uORF. These findings suggest that GADD34 translation is regulated by a unique 5′UTR uORF mechanism to ensure proper GADD34 expression during eIF2α phosphorylation. This mechanism may serve as a model for understanding how other 5′UTR uORF-containing mRNAs are regulated during cellular stress. Phosphorylation of Ser51 in eIF2α is a key cellular response to environmental stresses such as hypoxia, endoplasmic reticulum (ER) 2The abbreviations used are: ER, endoplasmic reticulum; PERK, protein kinase R-like ER kinase; eIF2α, eukaryotic initiation factor 2α; ORF, open reading frame; uORF, upstream ORF; UTR, untranslated region; UPR, unfolded protein response; RACE, rapid amplification of cDNA ends; YFP, yellow fluorescent protein; DTT, dithiothreitol; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IRES, internal ribosome entry site; C/EBP, CAAT/enhancer-binding protein; GADD34, growth arrest DNA-inducible gene 34. stress and viral infection. The stress-induced phosphorylation of eIF2α represses general protein synthesis, which induces the expression of specific genes involved in the stress response (1Ron D. Harding H.P. Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: 345-368Google Scholar, 2Dever T.E. Dar A.C. Sicheri F. Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: 319-344Google Scholar). Reprogramming of gene expression is vital for cellular survival and can trigger apoptosis, if the stress is severe and prolonged. In mammals, four distinct eIF2α kinases have been identified (2Dever T.E. Dar A.C. Sicheri F. Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: 319-344Google Scholar). These include protein kinase R, which is activated upon binding to double-stranded RNAs or through the antiviral interferon response (3Kostura M. Mathews M.B. Mol. Cell. Biol. 1989; 9: 1576-1586Crossref PubMed Scopus (162) Google Scholar), the heme-regulated inhibitor, which senses heme availability and responds to oxidative stress (4Han A.P. Yu C. Lu L. Fujiwara Y. Browne C. Chin G. Fleming M. Leboulch P. Orkin S.H. Chen J.J. EMBO J. 2001; 20: 6909-6918Crossref PubMed Scopus (276) Google Scholar, 5Chen J.J. L. M. PubMed Scopus Google Scholar), the general which is regulated by availability T.E. L. Cell. PubMed Scopus Google Scholar), and the protein kinase R-like ER PERK, which is activated in response to an of unfolded in the ER H.P. Y. D. PubMed Scopus Google Scholar). protein kinase R, heme-regulated inhibitor, general and can the phosphorylation of eIF2α to protein synthesis, in response to distinct environmental the of unfolded in the ER activates to translation to the of unfolded in the ER, whereas repression during is through general which for The of eIF2α kinase is in with such as and viral and J. PubMed Scopus Google Scholar, H.P. Y. P. D. Mol. Cell. 2001; PubMed Scopus Google Scholar, Sonenberg N. Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: Scholar, D. C. P. Mol. Cell. 2001; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). The of and the initiation factor mediates of the by scanning (2Dever T.E. Dar A.C. Sicheri F. Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: 319-344Google Scholar, Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: Scholar). of the of the is to and is to the fluorescent by the Phosphorylation of the of eIF2α Ser51 the of for by the of and protein synthesis Biol. PubMed Scopus Google Scholar, J. Biol. PubMed Google Scholar). general protein synthesis is eIF2α is a subset of mRNAs translated mRNAs include ATF4, and mRNAs T.E. L. Cell. PubMed Scopus Google Scholar, H.P. Y. M. D. Mol. Cell. PubMed Scopus Google Scholar, Harding H.P. D. J. Biol. PubMed Scopus Google Scholar, D. L. J. J. Biol. PubMed Scopus Google Scholar, Y. N. M. N. Y. J. Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of ATF4, a of the of transcription for transcription of downstream is by two its 5′UTR Harding H.P. D. J. Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). translation of the upstream uORF, basal ribosomes scanning and translation the downstream uORF, which leads to ribosome and In eIF2α is ribosomes have a of downstream the of the downstream uORF and translation the This mechanism is of the model of by the of the transcription factor Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: Scholar). The expression of is also regulated the through a mechanism in its that such a mechanism is and for mRNAs D. L. J. J. Biol. PubMed Scopus Google Scholar, Y. N. M. N. Y. J. Biol. PubMed Scopus Google Scholar). The of unfolded in the ER activates a of to as the unfolded protein response M. M. L. C. N. G. PubMed Scopus Google Scholar). of the the unfolded protein PERK, to protein synthesis eIF2α phosphorylation, which in turn induces translation H.P. Y. M. D. Mol. Cell. PubMed Scopus Google Scholar). activates the transcription of downstream stress-induced and GADD34 H.P. Y. Lu M. N. C. D. Mol. Cell. PubMed Scopus Google Scholar). GADD34 interacts with protein phosphatase 1 to dephosphorylate eIF2α, which the of translation Harding D. J. Biol. 2001; PubMed Scopus Google Scholar, Y. J. Biol. PubMed Scopus Google Scholar). This negative feedback loop is for translation of stress-induced genes and to ER stress Harding D. J. Biol. 2001; PubMed Scopus Google Scholar, Y. J. Biol. PubMed Scopus Google Scholar, Y. Harding H.P. D. EMBO J. PubMed Scopus Google Scholar, C. Y. Harding D. PubMed Scopus Google Scholar). is that GADD34 is the mechanism by which the GADD34 is translated during eIF2α phosphorylation In this we that translation of the human and mouse GADD34 mRNAs are through an uORF its which is for repression during and directs translation of GADD34 during eIF2α phosphorylation. suggest that the human and mouse a distinct mechanism to ensure GADD34 expression during cellular stresses that eIF2α phosphorylation. and human 5′UTR mouse 5′UTR and human 5′UTR reporter a in the The human GADD34 5′UTR cDNA by the and a and the The and The human GADD34 5′UTR with and The mouse GADD34 5′UTR cDNA and which a The human 5′UTR and and 5′UTR with a and a which contains with The reporter YFP, a and a The 5′UTR and and of resulting in of the 5′UTR with an The contains the of These the human GADD34 the mouse GADD34 and the human that out the of uORF, the and of the mouse or uORF with the ORF, the and The of the is The of with the of the 1 and a to and and by and in with and of in and as with 1 DTT, or to eIF2α kinases and eIF2α phosphorylation. two with and 1 and a The and to and by and to a or eIF2α a to the of eIF2α and eIF2α with an with GADD34 and fluorescent protein The fluorescent protein with the reporter and and as G. M.B. P. PubMed Scopus Google Scholar). to and to with for with and the 1 and by for and the resulting a of the the The for in an the an and a of and of to and in of to and of in and with for and with for stress, 1 DTT, or the in and two with and in 1 DTT, 1 and of by with fluorescent protein and to the by to the by in and by The to and by or a and to the The of by and Translational Control during ER in the of during ER stress, human and mouse with or These are and are to that unfolded in the synthesis by with for the by of the and general protein synthesis as as and for and with phosphorylation of eIF2α and in protein synthesis upon with or which with phosphorylation of eIF2α with or for also an in GADD34 protein with the that GADD34 protein eIF2α Y. Harding H.P. D. EMBO J. PubMed Scopus Google expression in during and of and of or with 1 or for the specific to GADD34, ATF4, and mRNAs to the and to the of the GADD34, ATF4, eIF2α, and by as to the of are GADD34, two are which of GADD34 protein and and The the of GADD34 and the by the GADD34 of a GADD34 The of GADD34 protein to the of GADD34 the of in or a with 1 or 1 as to the The of GADD34 and mRNAs is by to of the are to of and polysomes the are the of the of is in the translation of specific and RNAs during ER stress, of or with by In the of ribosomes to that ribosomes are in translation In of with in of ribosomes mRNAs and an in and The of polysomes is in with the in protein synthesis during of GADD34 in and during ER GADD34 mRNAs are associated with polysomes during ER stress. the of specific mRNAs with mRNAs the by In human and mouse and mRNAs to and that mRNAs associated with ribosomes and are translated and in a of and mRNAs to with mRNAs translationally to in associated with polysomes during and in as and H.P. Y. M. D. Mol. Cell. PubMed Scopus Google Scholar, Harding H.P. D. J. Biol. PubMed Scopus Google Scholar). In with ribosomes ER stress that this is translationally induced during eIF2α phosphorylation to ATF4, human and mouse GADD34 mRNAs to during and with during like ATF4, human and mouse GADD34 mRNAs to translation during ER stress eIF2α is GADD34 the and Translational during ER that the GADD34 associated with ribosomes and that GADD34 been to transcriptionally during ER stress Harding D. J. Biol. 2001; PubMed Scopus Google Scholar, Y. J. Biol. PubMed Scopus Google Scholar), the in GADD34 protein expression is to in transcription and translation the of of GADD34 during eIF2α phosphorylation, we with the transcription inhibitor, and with the transcription of GADD34, ATF4, and with that genes are transcriptionally induced during ER stress and H.P. Y. M. D. Mol. Cell. PubMed Scopus Google Scholar, Harding D. J. Biol. 2001; PubMed Scopus Google Scholar). of with or a of and induced a but in GADD34 protein that GADD34 is translationally and with not GADD34 protein expression during and whereas expression only induced during in that is for expression during ER stress H.P. Y. M. D. Mol. Cell. PubMed Scopus Google Scholar). The of GADD34 and protein during not as as during and that of GADD34 and is for maximal expression during eIF2α phosphorylation. 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PubMed Scopus Google Scholar, P. J. Mol. Biol. PubMed Scopus Google Scholar, J. P. M. J. Biol. PubMed Scopus Google Scholar). the mechanism the 5′UTR translation during eIF2α phosphorylation Harding H.P. D. J. Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of reporter RNAs during eIF2α phosphorylation, the in expression to in and of the during ER stress protein synthesis by The two and the 5′UTR are of the non-overlapping the and mouse in that are by a have that an of only the for the scanning ribosomes to the of the downstream uORF, during basal is Mol. Cell. Biol. PubMed Scopus Google Scholar, M. Mol. Cell. Biol. PubMed Scopus Google Scholar, A.P. J. Biol. PubMed Scopus Google Scholar). This a model represses that the the two the 5′UTR is not in which may for the repression basal this that the downstream uORF, we the of 5′UTR are we the of the upstream or downstream to the or and basal translation to translation whereas an translation as with the reporter in which are and This is in to the upstream uORF of ATF4, which the downstream Harding H.P. D. J. Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). the of the is to that of ATF4, that the mechanism of repression of is distinct that of and may not the downstream uORF. 5′UTR or translation during with basal an the GADD34 5′UTR translation during ER stress and In translation of the to the reporter uORFs. In the reporter during this and the downstream during and translation of GADD34 during eIF2α phosphorylation. 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The of translation of GADD34 to of the and that the 5′UTR represses translation of and to basal of that not inhibit scanning not that ribosome translation of a to the ribosomes may the and an scanning M. J. Biol. PubMed Google Scholar). The for by scanning ribosomes are the the the Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: Scholar, M. PubMed Scopus Google Scholar, M. Cell. PubMed Scopus Google Scholar). 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Paradoxically, eIF2α phosphorylation activates the translation of a subset of mRNAs and which transcription that downstream key of this cellular response is the of GADD34 protein In this we that GADD34 is in mediated through a 5′UTR mechanism that translation during ER stress. GADD34 mRNAs with and to polysomes during and ER stress that GADD34 is translated of general arrest eIF2α is the 5′UTR of human and mouse GADD34 mRNAs is and to translation during ER stress. reporter constructs, we that the GADD34 5′UTR induced of reporter mRNAs to polysomes during eIF2α phosphorylation, which is to the of GADD34 mRNAs and with M. J. P. C. Sonenberg N. EMBO J. PubMed Scopus Google Scholar), the that of GADD34 translation during eIF2α phosphorylation an in the general stress response, which cellular stress, ER stress, oxidative stress, and GADD34 is an of the Harding D. J. Biol. 2001; PubMed Scopus Google Scholar, Y. Harding H.P. D. EMBO J. PubMed Scopus Google Scholar). GADD34 interacts with protein phosphatase 1 its region to dephosphorylate eIF2α, to Harding D. J. Biol. 2001; PubMed Scopus Google Scholar, Y. Harding H.P. D. EMBO J. PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). expression of a GADD34 protein the region in mouse eIF2α and during ER stress, resulting in Harding D. J. Biol. 2001; PubMed Scopus Google Scholar). The to is to repression of stress-induced such as the which are during ER stress Y. Harding H.P. D. EMBO J. PubMed Scopus Google Scholar). the expression of GADD34 in a negative feedback loop to the translation of stress-induced mRNAs during eIF2α phosphorylation, which are for cellular survival and to environmental stress. GADD34 is also regulated the which is induced in by and which are during ER stress Y. J. Biol. PubMed Scopus Google Scholar, C. Y. Harding D. 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In as to scanning ribosomes translation of the cellular ribosomes can the and translation the The mechanism of is the ATF4, and The of this mechanism is that the translation of the upstream uORF translation or a downstream whereas translation of the downstream uORF leads to translation and of translation of the upstream uORF, if eIF2α is the of the by the ribosome is and as a ribosomes have a of translation the downstream uORF and translation the that the of are the the and the of the upstream uORF. translation of the of the downstream the of the to allow for scanning ribosomes to the Mol. Cell. Biol. PubMed Scopus Google Scholar, M. Mol. Cell. Biol. PubMed Scopus Google Scholar, A.P. J. Biol. PubMed Scopus Google Scholar). The the the that scanning ribosomes of this mechanism is that the of the the uORF, whereas with translation of Mathews M.B. Sonenberg N. Hershey J. Translational Control in Biology and Medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2007: Scholar, M. 2001; PubMed Scopus Google Scholar). ATF4, and uORFs. been that ribosomes that a uORF are to initiation which PubMed Scopus Google Scholar). are the PubMed Scopus Google Scholar). that the two the human and mouse GADD34 translation through a mechanism that is distinct the the human GADD34 the mouse GADD34 5′UTR can and In the human scanning ribosomes as with a 5′UTR with human and mouse are poorly translated and a proportion of ribosomes to translation a downstream In the of is which is a for the basal and the during eIF2α phosphorylation Harding H.P. D. J. Biol. 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These that scanning the GADD34 5′UTR to and translation The of GADD34 is a for scanning which represses GADD34 translation basal is ribosomes translation of the GADD34 the may other is been that the uORF in mRNAs that a of translation by scanning ribosomes and Mol. Cell. 20: PubMed Scopus Google Scholar, EMBO J. 2001; 20: PubMed Scopus Google Scholar). In this the translated of the uORF P. J. Biol. PubMed Scopus Google Scholar, P. C. PubMed Scopus Google Scholar). a of GADD34 that is The and GADD34 non-overlapping and the mouse and overlapping uORFs. the in and are poorly the are and to the or a in during eIF2α phosphorylation. The of of the that is mediated by this uORF is a the GADD34 is that an a of cellular stress is how scanning ribosomes and the GADD34 eIF2α is the that can eIF2α phosphorylation have been such mechanism that ribosomes are to the 5′UTR downstream of through an The unique is the region IRES, which can the for initiation to the ribosome and can translation during eIF2α phosphorylation J. P. M. J. Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). is In response to translation of is which is mediated in by an its 5′UTR and translation of an uORF J. M. L. D. M. Cell. PubMed Scopus Google Scholar). that an mechanism not GADD34 an uORF the 5′UTR of and can also translation during eIF2α phosphorylation Harding H.P. D. J. Biol. PubMed Scopus Google Scholar, Cell. PubMed Scopus Google Scholar). the transcription and are also regulated by a uORF in response to eIF2α phosphorylation C. Google Scholar, Harding H.P. Y. M. D. PubMed Scopus Google Scholar). These are poorly and to distinct the mechanism Harding H.P. D. J. Biol. PubMed Scopus Google Scholar). are to the and the GADD34 5′UTR The that and GADD34 expression that GADD34 is of GADD34 leads to in PubMed Scopus Google Scholar, Mol. Cell. Biol. PubMed Scopus Google Scholar, J. Biol. PubMed Scopus Google Scholar), and expression of the region of GADD34 in in in the Harding H.P. Y. M. D. PubMed Scopus Google Scholar). that the 5′UTR basal GADD34 expression during and is in the for expression during cellular stress. that are in of of GADD34 uORF is M. F. G. PubMed Scopus Google Scholar). The of the GADD34 5′UTR mechanism may how other stress-induced mRNAs are translated during eIF2α phosphorylation. and for reading of the the mouse and the

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