ATF4 is an oxidative stress–inducible, prodeath transcription factor in neurons in vitro and in vivo

Burke Medical Research Institute, White Plains, NY 10605, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2008; 205(5):1227-42. DOI: 10.1084/jem.20071460
Source: PubMed

ABSTRACT Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress-inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress-induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. In ATF4(-/-) neurons, restoration of ATF4 protein expression reinstated sensitivity to oxidative death. In addition, ATF4(-/-) mice experienced significantly smaller infarcts and improved behavioral recovery as compared with wild-type mice subjected to the same reductions in blood flow in a rodent model of ischemic stroke. Collectively, these findings establish ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.

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    • "As in other tissues, ATF4 plays multiple roles in brain. It is induced in neurons by stress and promotes cell survival or death (Lange et al., 2008; Ogawa et al., 2008; Galehdar et al., 2010; Sun et al., 2013). ATF4 is upregulated in neurodegenerative disorders including Parkinson's and Alzheimer's diseases (Lewerenz and Maher, 2009; Yoon et al., 2012; Sun et al., 2013), but its role(s) in these maladies remains undefined. "
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    ABSTRACT: The ubiquitously expressed activating transcription factor 4 (ATF4) has been variably reported to either promote or inhibit neuronal plasticity and memory. However, the potential cellular bases for these and other actions of ATF4 in brain are not well-defined. In this report, we focus on ATF4's role in post-synaptic synapse development and dendritic spine morphology. shRNA-mediated silencing of ATF4 significantly reduces the densities of PSD-95 and GluR1 puncta (presumed markers of excitatory synapses) in long-term cultures of cortical and hippocampal neurons. ATF4 knockdown also decreases the density of mushroom spines and increases formation of abnormally-long dendritic filopodia in such cultures. In vivo knockdown of ATF4 in adult mouse hippocampal neurons also reduces mushroom spine density. In contrast, ATF4 over-expression does not affect the densities of PSD-95 puncta or mushrooom spines. Regulation of synaptic puncta and spine densities by ATF4 requires its transcriptional activity and is mediated at least in part by indirectly controlling the stability and expression of the total and active forms of the actin regulatory protein Cdc42. In support of such a mechanism, ATF4 silencing decreases the half-life of Cdc42 in cultured cortical neurons from 31.5 to 18.5 h while knockdown of Cdc42, like ATF4 knockdown, reduces the densities of mushroom spines and PSD-95 puncta. Thus, ATF4 appears to participate in neuronal development and plasticity by regulating the post-synaptic development of synapses and dendritic mushroom spines via a mechanism that includes regulation of Cdc42 levels.
    Frontiers in Cellular Neuroscience 06/2014; 8:177. DOI:10.3389/fncel.2014.00177 · 4.29 Impact Factor
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    • "Many novel ER stress-inducible factors have been rapidly identified and characterized because ER stress has been implicated in the onset and progression of diseases, such as neurodegenerative and inflammations (Lange et al. 2008; Woo et al. 2009). Although several ER stress-inducible secretory factors, including CRELD2 (Maslen et al. 2006; Ortiz et al. 2005; Oh-hashi et al. 2011), mesencephalic astrocyte-derived neurotrophic factor (Mizobuchi et al. 2007) and nucleobindin 1 (Tsukumo et al. 2007), have been identified, the regulation of their intracellular transportation and secretion as well as their precise functions have not been elucidated well. "
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    ABSTRACT: We previously demonstrated that cysteine-rich with EGF-like domains 2 (CRELD2), a novel ER stress-inducible factor, is a secretory glycoprotein; however, the stimuli that induce CRELD2 secretion have not yet been characterized. In this study, we found that the perturbation of intravesicular acidification of cytoplasmic organelles in HEK293 cells stably expressing wild-type (wt) CRELD2 induced its secretion. In particular, Concanamycin A (CMA) and Bafilomycin A1 (Baf), inhibitors of vacuolar ATPase (V-ATPase), increased the secretion of CRELD2 without relying on its C-terminal structure. The levels of secretion of EGFP-fused CRELD2 (SP-EGFP-CRELD2), which consists of EGFP following the putative signal peptide (SP) sequence of CRELD2, from COS7 cells transiently transfected with this construct were also increased after each of the treatments, but their intracellular localization was barely affected by CMA treatment. Transient overexpression of 78-kDa glucose-regulated protein (GRP78) and protein disulfide isomerase (PDI) also increased the secretion of CRELD2 from HEK293 cells expressing wt CRELD2, whereas the perturbation of intravesicular acidification did not alter the expression of GRP78 and PDI in the HEK293 cells. We further studied the roles of intracellular calcium ions and the Golgi apparatus in the secretion of CRELD2 from HEK293 cells in which intravesicular acidification was perturbed. The treatment with calcium ionophore increased the secretion of wt CRELD2, while that with BAPTA-AM, an intracellular calcium chelator, did not reduce the CMA-induced CRELD2 secretion. By contrast, treatment with brefeldin A (BFA), which inhibits the transportation of proteins from the ER to the Golgi apparatus, almost completely abolished the secretion of wt CRELD2 from the HEK293 cells. In conclusion, we demonstrated that the intravesicular acidification by V-ATPase regulates the secretion of CRELD2 without relying on the balance of intracellular calcium ions and the expression of ER chaperones such as GRP78 and PDI. These findings concerning the role of V-ATPases in modulating the secretion of CRELD2, a novel ER stress-inducible secretory factor, may provide new insights into the prevention and treatment of certain ER stress-related diseases.
    Cell Biology and Toxicology 04/2014; 30(3). DOI:10.1007/s10565-014-9274-5 · 2.68 Impact Factor
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    • "Sustained PERK signaling also contributes to apoptosis by enhancing oxidative stress and by resuming protein synthesis after prolonged ER stress [18], [19], [20]. Although PERK deficiency enhances the susceptibility of cells to apoptosis in mouse embryonic fibroblasts [11], its expression in neurons has been shown to operate as a central regulator of oxidative stress genes affecting cell survival during hypoxia [21]. In contrast, another study suggested that CHOP could also have a neuroprotective activity against hypoxia [22]. "
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    ABSTRACT: Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1(G86R) transgenic mice. The fraction of ATF4(-/-)-SOD1(G85R) transgenic mice that were born are more resistant to develop ALS, leading to delayed disease onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34 demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention.
    PLoS ONE 07/2013; 8(7):e66672. DOI:10.1371/journal.pone.0066672 · 3.23 Impact Factor
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