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Journal articles on the topic 'ATF6α'

Author: Grafiati

Published: 7 December 2024

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1

Amyot, Julie, Isma Benterki, Ghislaine Fontés, Derek K. Hagman, Mourad Ferdaoussi, Tracy Teodoro, Allen Volchuk, Érik Joly, and Vincent Poitout. "Binding of activating transcription factor 6 to the A5/Core of the rat insulin II gene promoter does not mediate its transcriptional repression." Journal of Molecular Endocrinology 47, no. 3 (August 5, 2011): 273–83. http://dx.doi.org/10.1530/jme-11-0016.

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Pancreatic β-cells have a well-developed endoplasmic reticulum due to their highly specialized secretory function to produce insulin in response to glucose and nutrients. It has been previously reported that overexpression of activating transcription factor 6 (ATF6) reduces insulin gene expression in part via upregulation of small heterodimer partner. In this study, we investigated whether ATF6 directly binds to the insulin gene promoter, and whether its direct binding represses insulin gene promoter activity. A bioinformatics analysis identified a putative ATF6 binding site in the A5/Core region of the rat insulin II gene promoter. Direct binding of ATF6 was confirmed using several approaches. Electrophoretic mobility shift assays in nuclear extracts from MCF7 cells, isolated rat islets and insulin-secreting HIT-T15 cells showed ATF6 binding to the native A5/Core of the rat insulin II gene promoter. Antibody-mediated supershift analyses revealed the presence of both ATF6 isoforms, ATF6α and ATF6β, in the complex. Chromatin immunoprecipitation assays confirmed the binding of ATF6α and ATF6β to a region encompassing the A5/Core of the rat insulin II gene promoter in isolated rat islets. Overexpression of the active (cleaved) fragment of ATF6α, but not ATF6β, inhibited the activity of an insulin promoter–reporter by 50%. However, the inhibitory effect of ATF6α was insensitive to mutational inactivation or deletion of the A5/Core. Therefore, although ATF6 binds directly to the A5/Core of the rat insulin II gene promoter, this direct binding does not appear to contribute to its repressive activity.

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2

Yoshida, Hiderou, Tetsuya Okada, Kyosuke Haze, Hideki Yanagi, Takashi Yura, Manabu Negishi, and Kazutoshi Mori. "Endoplasmic Reticulum Stress-Induced Formation of Transcription Factor Complex ERSF Including NF-Y (CBF) and Activating Transcription Factors 6α and 6β That Activates the Mammalian Unfolded Protein Response." Molecular and Cellular Biology 21, no. 4 (February 15, 2001): 1239–48. http://dx.doi.org/10.1128/mcb.21.4.1239-1248.2001.

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ABSTRACT The levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) are controlled by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element (ERSE), the consensus sequence of which is CCAAT-N9-CCACG. We recently proposed that ER stress response factor (ERSF) binding to ERSE is a heterologous protein complex consisting of the constitutive component NF-Y (CBF) binding to CCAAT and an inducible component binding to CCACG and identified the basic leucine zipper-type transcription factors ATF6α and ATF6β as inducible components of ERSF. ATF6α and ATF6β produced by ER stress-induced proteolysis bind to CCACG only when CCAAT is bound to NF-Y, a heterotrimer consisting of NF-YA, NF-YB, and NF-YC. Interestingly, the NF-Y and ATF6 binding sites must be separated by a spacer of 9 bp. We describe here the basis for this strict requirement by demonstrating that both ATF6α and ATF6β physically interact with NF-Y trimer via direct binding to the NF-YC subunit. ATF6α and ATF6β bind to the ERSE as a homo- or heterodimer. Furthermore, we showed that ERSF including NF-Y and ATF6α and/or β and capable of binding to ERSE is indeed formed when the cellular UPR is activated. We concluded that ATF6 homo- or heterodimers recognize and bind directly to both the DNA and adjacent protein NF-Y and that this complex formation process is essential for transcriptional induction of ER chaperones.

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3

Lee, Ann-Hwee, Neal N. Iwakoshi, and Laurie H. Glimcher. "XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7448–59. http://dx.doi.org/10.1128/mcb.23.21.7448-7459.2003.

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ABSTRACT The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER). We have investigated here the contribution of the UPR transcription factors XBP-1, ATF6α, and ATF6β to UPR target gene expression. Gene profiling of cell lines lacking these factors yielded several XBP-1-dependent UPR target genes, all of which appear to act in the ER. These included the DnaJ/Hsp40-like genes, p58IPK, ERdj4, and HEDJ, as well as EDEM, protein disulfide isomerase-P5, and ribosome-associated membrane protein 4 (RAMP4), whereas expression of BiP was only modestly dependent on XBP-1. Surprisingly, given previous reports that enforced expression of ATF6α induced a subset of UPR target genes, cells deficient in ATF6α, ATF6β, or both had minimal defects in upregulating UPR target genes by gene profiling analysis, suggesting the presence of compensatory mechanism(s) for ATF6 in the UPR. Since cells lacking both XBP-1 and ATF6α had significantly impaired induction of select UPR target genes and ERSE reporter activation, XBP-1 and ATF6α may serve partially redundant functions. No UPR target genes that required ATF6β were identified, nor, in contrast to XBP-1 and ATF6α, did the activity of the UPRE or ERSE promoters require ATF6β, suggesting a minor role for it during the UPR. Collectively, these results suggest that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP-1. Further, our observations suggest the existence of additional, as-yet-unknown, key regulators of the UPR.

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4

Ishikawa, Tokiro, Tetsuya Okada, Tomoko Ishikawa-Fujiwara, Takeshi Todo, Yasuhiro Kamei, Shuji Shigenobu, Minoru Tanaka, et al. "ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish." Molecular Biology of the Cell 24, no. 9 (May 2013): 1387–95. http://dx.doi.org/10.1091/mbc.e12-11-0830.

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ATF6α and ATF6β are membrane-bound transcription factors activated by regulated intramembrane proteolysis in response to endoplasmic reticulum (ER) stress to induce various ER quality control proteins. ATF6α- and ATF6β single-knockout mice develop normally, but ATF6α/β double knockout causes embryonic lethality, the reason for which is unknown. Here we show in medaka fish that ATF6α is primarily responsible for transcriptional induction of the major ER chaperone BiP and that ATF6α/β double knockout, but not ATF6α- or ATF6β single knockout, causes embryonic lethality, as in mice. Analyses of ER stress reporters reveal that ER stress occurs physiologically during medaka early embryonic development, particularly in the brain, otic vesicle, and notochord, resulting in ATF6α- and ATF6β-mediated induction of BiP, and that knockdown of the α1 chain of type VIII collagen reduces such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6α/β double knockout causes more profound ER stress and impaired notochord development, which is partially rescued by overexpression of BiP. Thus ATF6α/β-mediated adjustment of chaperone levels to increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra.

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5

Sharma, Rohit B., Christine Darko, and Laura C. Alonso. "Intersection of the ATF6 and XBP1 ER stress pathways in mouse islet cells." Journal of Biological Chemistry 295, no. 41 (August 11, 2020): 14164–77. http://dx.doi.org/10.1074/jbc.ra120.014173.

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Success or failure of pancreatic beta cell adaptation to ER stress is a determinant of diabetes susceptibility. The ATF6 and IRE1/XBP1 pathways are separate ER stress-response effectors important to beta cell health and function. ATF6α. and XBP1 direct overlapping transcriptional responses in some cell types. However, the signaling dynamics and interdependence of ATF6α and XBP1 in pancreatic beta cells have not been explored. To assess pathway-specific signal onset, we performed timed exposures of primary mouse islet cells to ER stressors and measured the early transcriptional response. Comparing the time course of induction of ATF6 and XBP1 targets suggested that the two pathways have similar response dynamics. The role of ATF6α in target induction was assessed by acute knockdown using islet cells from Atf6αflox/flox mice transduced with adenovirus expressing Cre recombinase. Surprisingly, given the mild impact of chronic deletion in mice, acute ATF6α knockdown markedly reduced ATF6-pathway target gene expression under both basal and stressed conditions. Intriguingly, although ATF6α knockdown did not alter Xbp1 splicing dynamics or intensity, it did reduce induction of XBP1 targets. Inhibition of Xbp1 splicing did not decrease induction of ATF6α targets. Taken together, these data suggest that the XBP1 and ATF6 pathways are simultaneously activated in islet cells in response to acute stress and that ATF6α is required for full activation of XBP1 targets, but XBP1 is not required for activation of ATF6α targets. These observations improve understanding of the ER stress transcriptional response in pancreatic islets.

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6

Teodoro, Tracy, Tanya Odisho, Elena Sidorova, and Allen Volchuk. "Pancreatic β-cells depend on basal expression of active ATF6α-p50 for cell survival even under nonstress conditions." American Journal of Physiology-Cell Physiology 302, no. 7 (April 1, 2012): C992—C1003. http://dx.doi.org/10.1152/ajpcell.00160.2011.

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Activating transcription factor 6 (ATF6) is one of three principle endoplasmic reticulum (ER) stress response proteins and becomes activated when ER homeostasis is perturbed. ATF6 functions to increase ER capacity by stimulating transcription of ER-resident chaperone genes such as GRP78. Using an antibody that recognizes active ATF6α-p50, we found that active ATF6α was detected in insulinoma cells and rodent islets even under basal conditions and the levels were further increased by ER stress. To examine the function of ATF6α-p50, we depleted endogenous ATF6α-p50 levels using small interfering RNA in insulinoma cells. Knockdown of endogenous ATF6α-p50 levels by ∼60% resulted in a reduction in the steady-state levels of GRP78 mRNA and protein levels in nonstressed cells. Furthermore, ATF6α knockdown resulted in an apoptotic phenotype. We hypothesized that removal of the ATF6α branch of the unfolded protein response (UPR) would result in ER stress. However, neither the PKR-like endoplasmic reticulum kinase (PERK), nor the inositol requiring enzyme 1 (IRE1) pathways of the UPR were significantly activated in ATF6α knockdown cells, although these cells were more sensitive to ER stress-inducing compounds. Interestingly, phosphorylation of JNK, p38, and c-Jun were elevated in ATF6α knockdown cells and inhibition of JNK or p38 kinases prevented apoptosis. These results suggest that ATF6α may have a role in maintaining β-cell survival even in the absence of ER stress.

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7

Xue, Fei, Jianwen Lu, Samuel C. Buchl, Liankang Sun, Vijay H. Shah, Harmeet Malhi, and Jessica L. Maiers. "Coordinated signaling of activating transcription factor 6α and inositol-requiring enzyme 1α regulates hepatic stellate cell-mediated fibrogenesis in mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 320, no. 5 (May 1, 2021): G864—G879. http://dx.doi.org/10.1152/ajpgi.00453.2020.

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ATF6α is a critical driver of hepatic stellate cell (HSC) activation in vitro. HSC-specific deletion of Atf6a limits fibrogenesis in vivo despite increased IRE1α signaling. Conditional deletion of Ire1α from HSCs limits fibrogenic gene transcription without impacting overall fibrosis. This could be due in part to observed upregulation of the ATF6α pathway. Dual loss of Atf6a and Ire1a from HSCs worsens fibrosis in vivo through enhanced HSC activation.

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8

Stauffer, Winston T., Adrian Arrieta, Erik A. Blackwood, and Christopher C. Glembotski. "Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6α." International Journal of Molecular Sciences 21, no. 3 (February 8, 2020): 1134. http://dx.doi.org/10.3390/ijms21031134.

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There are more than 2000 transcription factors in eukaryotes, many of which are subject to complex mechanisms fine-tuning their activity and their transcriptional programs to meet the vast array of conditions under which cells must adapt to thrive and survive. For example, conditions that impair protein folding in the endoplasmic reticulum (ER), sometimes called ER stress, elicit the relocation of the ER-transmembrane protein, activating transcription factor 6α (ATF6α), to the Golgi, where it is proteolytically cleaved. This generates a fragment of ATF6α that translocates to the nucleus, where it regulates numerous genes that restore ER protein-folding capacity but is degraded soon after. Thus, upon ER stress, ATF6α is converted from a stable, transmembrane protein, to a rapidly degraded, nuclear protein that is a potent transcription factor. This review focuses on the molecular mechanisms governing ATF6α location, activity, and stability, as well as the transcriptional programs ATF6α regulates, whether canonical genes that restore ER protein-folding or unexpected, non-canonical genes affecting cellular functions beyond the ER. Moreover, we will review fascinating roles for an ATF6α isoform, ATF6β, which has a similar mode of activation but, unlike ATF6α, is a long-lived, weak transcription factor that may moderate the genetic effects of ATF6α.

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9

Azuma, Yoshinori, Daisuke Hagiwara, Wenjun Lu, Yoshiaki Morishita, Hidetaka Suga, Motomitsu Goto, Ryoichi Banno, et al. "Activating Transcription Factor 6α Is Required for the Vasopressin Neuron System to Maintain Water Balance Under Dehydration in Male Mice." Endocrinology 155, no. 12 (December 1, 2014): 4905–14. http://dx.doi.org/10.1210/en.2014-1522.

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Activating transcription factor 6α (ATF6α) is a sensor of endoplasmic reticulum (ER) stress and increases the expression of ER chaperones and molecules related to the ER-associated degradation of unfolded/misfolded proteins. In this study, we used ATF6α knockout (ATF6α−/−) mice to clarify the role of ATF6α in the arginine vasopressin (AVP) neuron system. Although urine volumes were not different between ATF6α−/− and wild-type (ATF6α+/+) mice with access to water ad libitum, they were increased in ATF6α−/− mice compared with those in ATF6α+/+ mice under intermittent water deprivation (WD) and accompanied by less urine AVP in ATF6α−/− mice. The mRNA expression of immunoglobulin heavy chain binding protein, an ER chaperone, was significantly increased in the supraoptic nucleus in ATF6α+/+ but not ATF6α−/− mice after WD. Electron microscopic analyses demonstrated that the ER lumen of AVP neurons was more dilated in ATF6α−/− mice than in ATF6α+/+ mice after WD. ATF6α−/− mice that were mated with mice possessing a mutation causing familial neurohypophysial diabetes insipidus (FNDI), which is characterized by progressive polyuria and AVP neuronal loss due to the accumulation of mutant AVP precursor in the ER, manifested increased urine volume under intermittent WD. The aggregate formation in the ER of AVP neurons was further impaired in FNDI/ATF6α−/− mice compared with that in FNDI mice, and AVP neuronal loss was accelerated in FNDI/ATF6α−/− mice under WD. These data suggest that ATF6α is required for the AVP neuron system to maintain water balance under dehydration.

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10

Pagliara, Valentina, Giuseppina Amodio, Vincenzo Vestuto, Silvia Franceschelli, Nicola Antonino Russo, Vittorio Cirillo, Giovanna Mottola, Paolo Remondelli, and Ornella Moltedo. "Myogenesis in C2C12 Cells Requires Phosphorylation of ATF6α by p38 MAPK." Biomedicines 11, no. 5 (May 16, 2023): 1457. http://dx.doi.org/10.3390/biomedicines11051457.

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Activating transcription factor 6α (ATF6α) is an endoplasmic reticulum protein known to participate in unfolded protein response (UPR) during ER stress in mammals. Herein, we show that in mouse C2C12 myoblasts induced to differentiate, ATF6α is the only pathway of the UPR activated. ATF6α stimulation is p38 MAPK-dependent, as revealed by the use of the inhibitor SB203580, which halts myotube formation and, at the same time, impairs trafficking of ATF6α, which accumulates at the cis-Golgi without being processed in the p50 transcriptional active form. To further evaluate the role of ATF6α, we knocked out the ATF6α gene, thus inhibiting the C2C12 myoblast from undergoing myogenesis, and this occurred independently from p38 MAPK activity. The expression of exogenous ATF6α in knocked-out ATF6α cells recover myogenesis, whereas the expression of an ATF6α mutant in the p38 MAPK phosphorylation site (T166) was not able to regain myogenesis. Genetic ablation of ATF6α also prevents the exit from the cell cycle, which is essential for muscle differentiation. Furthermore, when we inhibited differentiation by the use of dexamethasone in C2C12 cells, we found inactivation of p38 MAPK and, consequently, loss of ATF6α activity. All these findings suggest that the p-p38 MAPK/ATF6α axis, in pathophysiological conditions, regulates myogenesis by promoting the exit from the cell cycle, an essential step to start myoblasts differentiation.

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HAZE, Kyosuke, Tetsuya OKADA, Hiderou YOSHIDA, Hideki YANAGI, Takashi YURA, Manabu NEGISHI, and Kazutoshi MORI. "Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response." Biochemical Journal 355, no. 1 (February 26, 2001): 19–28. http://dx.doi.org/10.1042/bj3550019.

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Eukaryotic cells control the levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element consisting of 19nt (CCAATN9CCACG), the CCACG part of which is considered to provide specificity. We recently identified the basic leucine zipper (bZIP) protein ATF6 as a mammalian UPR-specific transcription factor; ATF6 is activated by ER stress-induced proteolysis and binds directly to CCACG. Here we report that eukaryotic cells express another bZIP protein closely related to ATF6 in both structure and function. This protein encoded by the G13 (cAMP response element binding protein-related protein) gene is constitutively synthesized as a type II transmembrane glycoprotein anchored in the ER membrane and processed into a soluble form upon ER stress as occurs with ATF6. The proteolytic processing of ATF6 and the G13 gene product is accompanied by their relocation from the ER to the nucleus; their basic regions seem to function as a nuclear localization signal. Overexpression of the soluble form of the G13 product constitutively activates the UPR, whereas overexpression of a mutant lacking the activation domain exhibits a strong dominant-negative effect. Furthermore, the soluble forms of ATF6 and the G13 gene product are unable to bind to several point mutants of the cis-acting ER stress response element in vitro that hardly respond to ER stress in vivo. We thus concluded that the two related bZIP proteins are crucial transcriptional regulators of the mammalian UPR, and propose calling the ATF6 gene product ATF6α and the G13 gene product ATF6β.

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Ekong, Udeme D., Jie Yao, James Knight, Sameet Mehta, Yaron Avitzur, Mercedes Martinez, Steve J. Lobritto, and Andrew Mason. "HERV1-env dependent unfolded protein response activation is a potential initiator of autoreactivity in autoimmune liver disease." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 224.7. http://dx.doi.org/10.4049/jimmunol.204.supp.224.7.

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Abstract Regulatory T cells are not terminally differentiated but can acquire effector properties. Here we report Human Endogenous Retrovirus 1 (HERV1-env) induction of endoplasmic reticulum (ER) stress with Unfolded Protein Response (UPR) activation, through its interaction with ATF6. UPR activation cleaves ATF6 to its α and β isoforms. ATF6α up-regulates RORC, STAT3 and TBX21 and induces IL-17A and INF-γ production in regulatory T cells by binding to promoter sequences. Silencing of HERV1-env results in partial recovery of regulatory T cell suppressive function and abrogation of apoptosis. These findings identify ER stress and UPR activation as key factors driving regulatory T cell plasticity.

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13

Thuerauf, Donna J., Lisa Morrison, and Christopher C. Glembotski. "Opposing Roles for ATF6α and ATF6β in Endoplasmic Reticulum Stress Response Gene Induction." Journal of Biological Chemistry 279, no. 20 (February 18, 2004): 21078–84. http://dx.doi.org/10.1074/jbc.m400713200.

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He, Yanfeng, Shigeo Sato, Chieri Tomomori-Sato, Shiyuan Chen, Zach H. Goode, Joan W. Conaway, and Ronald C. Conaway. "Elongin functions as a loading factor for Mediator at ATF6α-regulated ER stress response genes." Proceedings of the National Academy of Sciences 118, no. 39 (September 20, 2021): e2108751118. http://dx.doi.org/10.1073/pnas.2108751118.

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The bZIP transcription factor ATF6α is a master regulator of endoplasmic reticulum (ER) stress response genes. In this report, we identify the multifunctional RNA polymerase II transcription factor Elongin as a cofactor for ATF6α-dependent transcription activation. Biochemical studies reveal that Elongin functions at least in part by facilitating ATF6α-dependent loading of Mediator at the promoters and enhancers of ER stress response genes. Depletion of Elongin from cells leads to impaired transcription of ER stress response genes and to defects in the recruitment of Mediator and its CDK8 kinase subunit. Taken together, these findings bring to light a role for Elongin as a loading factor for Mediator during the ER stress response.

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Yamamoto, Keisuke, Kazuna Takahara, Seiichi Oyadomari, Tetsuya Okada, Takashi Sato, Akihiro Harada, and Kazutoshi Mori. "Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress." Molecular Biology of the Cell 21, no. 17 (September 2010): 2975–86. http://dx.doi.org/10.1091/mbc.e09-02-0133.

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Accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates homeostatic responses collectively termed the unfolded protein response. Among the three principal signaling pathways operating in mammals, activating transcription factor (ATF)6α plays a pivotal role in transcriptional induction of ER-localized molecular chaperones and folding enzymes as well as components of ER-associated degradation, and thereby mouse embryonic fibroblasts deficient in ATF6α are sensitive to ER stress. However, ATF6α-knockout mice show no apparent phenotype under normal growing conditions. In this report, we burdened mice with intraperitoneal injection of the ER stress-inducing reagent tunicamycin and found that wild-type mice were able to recover from the insult, whereas ATF6α-knockout mice exhibited liver dysfunction and steatosis. Thus, ATF6α-knockout mice accumulated neutral lipids in the liver such as triacylglycerol and cholesterol, which was ascribable to blockage of β-oxidation of fatty acids caused by decreased mRNA levels of the enzymes involved in the process, suppression of very-low-density lipoprotein formation due to destabilized apolipoprotein B-100, and stimulation of lipid droplet formation resulting from transcriptional induction of adipose differentiation-related protein. Accordingly, the hepatocytes of tunicamycin-injected knockout mice were filled with many lipid droplets. These results establish links among ER stress, lipid metabolism, and steatosis.

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Kim, Ju Won, So-Hyun Bae, Yesol Moon, Eun Kyung Kim, Yongjin Kim, Yun Gyu Park, Mi-Ryung Han, and Jeongwon Sohn. "Transcriptomic analysis of cellular senescence induced by ectopic expression of ATF6α in human breast cancer cells." PLOS ONE 19, no. 10 (October 28, 2024): e0309749. http://dx.doi.org/10.1371/journal.pone.0309749.

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Background The transcriptomic profile of cellular senescence is strongly associated with distinct cell types, the specific stressors triggering senescence, and temporal progression through senescence stages. This implies the potential necessity of conducting separate investigations for each cell type and a stressor inducing senescence. To elucidate the molecular mechanism that drives endoplasmic reticulum (ER) stress-induced cellular senescence in MCF-7 breast cancer cells, with a particular emphasis on the ATF6α branch of the unfolded protein response. We conducted transcriptomic analysis on MCF-7 cells by ectopic expression of ATF6α. Methods Transcriptomic sequencing was conducted on MCF-7 cells at 6 and 9 hours post senescence induction through ATF6α ectopic expression. Comprehensive analyses encompassing enriched functional annotation, canonical pathway analysis, gene network analysis, upstream regulator analysis and gene set enrichment analysis were performed on Differentially Expressed Genes (DEGs) at 6 and 9 hours as well as time-related DEGs. Regulators and their targets identified from the upstream regulator analysis were validated through RNA interference, and their impact on cellular senescence was assessed by senescence-associated β-galactosidase staining. Results ATF6α ectopic expression resulted in the identification of 12 and 79 DEGs at 6 and 9 hours, respectively, employing criteria of a false discovery rate < 0.05 and a lower fold change (FC) cutoff |log2FC| > 1. Various analyses highlighted the involvement of the UPR and/or ER Stress Pathway. Upstream regulator analysis of 9 hour-DEGs identified six regulators and eleven target genes associated with processes related to cytostasis and ‘cell viability and cell death of connective tissue cells.’ Validation confirmed the significance of MAP2K1/2, GPAT4, and PDGF-BB among the regulators and DDIT3, PPP1R15A, and IL6 among the targets. Conclusion Transcriptomic analyses and validation reveal the importance of the MAP2K1/2/GPAT4-DDIT3 pathway in driving cellular senescence following ATF6α ectopic expression in MCF-7 cells. This study contributes to our understanding of the initial molecular events underlying ER stress-induced cellular senescence in breast cancer cells, providing a foundation for exploring cell type- and stressor-specific responses in cellular senescence induction.

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Forouhan, M., K. Mori, and R. P. Boot-Handford. "Paradoxical roles of ATF6α and ATF6β in modulating disease severity caused by mutations in collagen X." Matrix Biology 70 (September 2018): 50–71. http://dx.doi.org/10.1016/j.matbio.2018.03.004.

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Guan, Dongyin, Hao Wang, Veronica E. Li, Yingying Xu, Min Yang, and Zonghou Shen. "N-glycosylation of ATF6β is essential for its proteolytic cleavage and transcriptional repressor function to ATF6α." Journal of Cellular Biochemistry 108, no. 4 (November 1, 2009): 825–31. http://dx.doi.org/10.1002/jcb.22310.

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Ninagawa, Satoshi, Tetsuya Okada, Yoshiki Sumitomo, Satoshi Horimoto, Takehiro Sugimoto, Tokiro Ishikawa, Shunichi Takeda, et al. "Forcible destruction of severely misfolded mammalian glycoproteins by the non-glycoprotein ERAD pathway." Journal of Cell Biology 211, no. 4 (November 16, 2015): 775–84. http://dx.doi.org/10.1083/jcb.201504109.

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Glycoproteins and non-glycoproteins possessing unfolded/misfolded parts in their luminal regions are cleared from the endoplasmic reticulum (ER) by ER-associated degradation (ERAD)-L with distinct mechanisms. Two-step mannose trimming from Man9GlcNAc2 is crucial in the ERAD-L of glycoproteins. We recently showed that this process is initiated by EDEM2 and completed by EDEM3/EDEM1. Here, we constructed chicken and human cells simultaneously deficient in EDEM1/2/3 and analyzed the fates of four ERAD-L substrates containing three potential N-glycosylation sites. We found that native but unstable or somewhat unfolded glycoproteins, such as ATF6α, ATF6α(C), CD3-δ–ΔTM, and EMC1, were stabilized in EDEM1/2/3 triple knockout cells. In marked contrast, degradation of severely misfolded glycoproteins, such as null Hong Kong (NHK) and deletion or insertion mutants of ATF6α(C), CD3-δ–ΔTM, and EMC1, was delayed only at early chase periods, but they were eventually degraded as in wild-type cells. Thus, higher eukaryotes are able to extract severely misfolded glycoproteins from glycoprotein ERAD and target them to the non-glycoprotein ERAD pathway to maintain the homeostasis of the ER.

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Sundaram, Arunkumar, Suhila Appathurai, Rachel Plumb, and Malaiyalam Mariappan. "Dynamic changes in complexes of IRE1α, PERK, and ATF6α during endoplasmic reticulum stress." Molecular Biology of the Cell 29, no. 11 (June 2018): 1376–88. http://dx.doi.org/10.1091/mbc.e17-10-0594.

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The endoplasmic reticulum (ER) localized unfolded protein response (UPR) sensors, IRE1α, PERK, and ATF6α, are activated by the accumulation of misfolded proteins in the ER. It is unclear how the endogenous UPR sensors are regulated by both ER stress and the ER luminal chaperone BiP, which is a negative regulator of UPR sensors. Here we simultaneously examined the changes in the endogenous complexes of UPR sensors by blue native PAGE immunoblotting in unstressed and stressed cells. We found that all three UPR sensors exist as preformed complexes even in unstressed cells. While PERK complexes shift to large complexes, ATF6α complexes are reduced to smaller complexes on ER stress. In contrast, IRE1α complexes were not significantly increased in size on ER stress, unless IRE1α is overexpressed. Surprisingly, depletion of BiP had little impact on the endogenous complexes of UPR sensors. In addition, overexpression of BiP did not significantly affect UPR complexes, but suppressed ER stress mediated activation of IRE1α, ATF6α and, to a lesser extent, PERK. Furthermore, we captured the interaction between IRE1α and misfolded secretory proteins in cells, which suggests that the binding of unfolded proteins to preformed complexes of UPR sensors may be crucial for activation.

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Bobrovnikova-Marjon, Ekaterina, and J. Alan Diehl. "Coping with Stress: ATF6α Takes the Stage." Developmental Cell 13, no. 3 (September 2007): 322–24. http://dx.doi.org/10.1016/j.devcel.2007.08.006.

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Liu, Pingting, Md Razaul Karim, Ana Covelo, Yuan Yue, Michael K. Lee, and Wensheng Lin. "The UPR Maintains Proteostasis and the Viability and Function of Hippocampal Neurons in Adult Mice." International Journal of Molecular Sciences 24, no. 14 (July 16, 2023): 11542. http://dx.doi.org/10.3390/ijms241411542.

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The unfolded protein response (UPR), which comprises three branches: PERK, ATF6α, and IRE1, is a major mechanism for maintaining cellular proteostasis. Many studies show that the UPR is a major player in regulating neuron viability and function in various neurodegenerative diseases; however, its role in neurodegeneration is highly controversial. Moreover, while evidence suggests activation of the UPR in neurons under normal conditions, deficiency of individual branches of the UPR has no major effect on brain neurons in animals. It remains unclear whether or how the UPR participates in regulating neuronal proteostasis under normal and disease conditions. To determine the physiological role of the UPR in neurons, we generated mice with double deletion of PERK and ATF6α in neurons. We found that inactivation of PERK and ATF6α in neurons caused lysosomal dysfunction (as evidenced by decreased expression of the V0a1 subunit of v-ATPase and decreased activation of cathepsin D), impairment of autophagic flux (as evidenced by increased ratio of LC3-II/LC3-I and increased p62 level), and accumulation of p-tau and Aβ42 in the hippocampus, and led to impairment of spatial memory, impairment of hippocampal LTP, and hippocampal degeneration in adult mice. These results suggest that the UPR is required for maintaining neuronal proteostasis (particularly tau and Aβ homeostasis) and the viability and function of neurons in the hippocampus of adult mice.

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MARUYAMA, Ryuto, Yuki KAMOSHIDA, Makoto SHIMIZU, Jun INOUE, and Ryuichiro SATO. "ATF6α Stimulates Cholesterogenic Gene Expression andde NovoCholesterol Synthesis." Bioscience, Biotechnology, and Biochemistry 77, no. 8 (August 23, 2013): 1734–38. http://dx.doi.org/10.1271/bbb.130295.

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Arai, Masaaki, Nobuo Kondoh, Nobuo Imazeki, Akiyuki Hada, Kazuo Hatsuse, Fumihiro Kimura, Osamu Matsubara, Kazutoshi Mori, Toru Wakatsuki, and Mikio Yamamoto. "Transformation-associated gene regulation by ATF6α during hepatocarcinogenesis." FEBS Letters 580, no. 1 (December 9, 2005): 184–90. http://dx.doi.org/10.1016/j.febslet.2005.11.072.

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Walter, Franziska, Aisling O'Brien, Caoimhín G. Concannon, Heiko Düssmann, and Jochen H. M. Prehn. "ER stress signaling has an activating transcription factor 6α (ATF6)-dependent “off-switch”." Journal of Biological Chemistry 293, no. 47 (October 4, 2018): 18270–84. http://dx.doi.org/10.1074/jbc.ra118.002121.

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In response to an accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen, three ER transmembrane signaling proteins, inositol-requiring enzyme 1 (IRE1), PRKR-like ER kinase (PERK), and activating transcription factor 6α (ATF6α), are activated. These proteins initiate a signaling and transcriptional network termed the unfolded protein response (UPR), which re-establishes cellular proteostasis. When this restoration fails, however, cells undergo apoptosis. To investigate cross-talk between these different UPR enzymes, here we developed a high-content live cell screening platform to image fluorescent UPR-reporter cell lines derived from human SH-SY5Y neuroblastoma cells in which different ER stress signaling proteins were silenced through lentivirus-delivered shRNA constructs. We observed that loss of ATF6 expression results in uncontrolled IRE1-reporter activity and increases X box–binding protein 1 (XBP1) splicing. Transient increases in both IRE1 mRNA and IRE1 protein levels were observed in response to ER stress, suggesting that IRE1 up-regulation is a general feature of ER stress signaling and was further increased in cells lacking ATF6 expression. Moreover, overexpression of the transcriptionally active N-terminal domain of ATF6 reversed the increases in IRE1 levels. Furthermore, inhibition of IRE1 kinase activity or of downstream JNK activity prevented an increase in IRE1 levels during ER stress, suggesting that IRE1 transcription is regulated through a positive feed-forward loop. Collectively, our results indicate that from the moment of activation, IRE1 signaling during ER stress has an ATF6-dependent “off-switch.”

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Jao, Tzu-Ming, Masaomi Nangaku, Chia-Hsien Wu, Mai Sugahara, Hisako Saito, Hiroshi Maekawa, Yu Ishimoto, et al. "ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis." Kidney International 95, no. 3 (March 2019): 577–89. http://dx.doi.org/10.1016/j.kint.2018.09.023.

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Papp, Sylvia, Xiaochu Zhang, Eva Szabo, Marek Michalak, and Michal Opas. "Expression of Endoplasmic Reticulum Chaperones in Cardiac Development." Open Cardiovascular Medicine Journal 2, no. 1 (May 21, 2008): 31–35. http://dx.doi.org/10.2174/1874192400802010031.

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To determine if cardiogenesis causes endoplasmic reticulum stress, we examined chaperone expression. Many cardiac pathologies cause activation of the fetal gene program, and we asked the reverse: could activation of the fetal gene program during development induce endoplasmic reticulum stress/chaperones? We found stress related chaperones were more abundant in embryonic compared to adult hearts, indicating endoplasmic reticulum stress during normal cardiac development. To determine the degree of stress, we investigated endoplasmic reticulum stress pathways during cardiogenesis. We detected higher levels of ATF6α, caspase 7 and 12 in adult hearts. Thus, during embryonic development, there is large protein synthetic load but there is no endoplasmic reticulum stress. In adult hearts, chaperones are less abundant but there are increased levels of ATF6α and ER stress-activated caspases. Thus, protein synthesis during embryonic development does not seem to be as intense a stress as is required for apoptosis that is found during postnatal remodelling.

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Gjymishka, Altin, Nan Su, and Michael S. Kilberg. "Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway." Biochemical Journal 417, no. 3 (January 16, 2009): 695–703. http://dx.doi.org/10.1042/bj20081706.

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The UPR (unfolded protein response) pathway comprises three signalling cascades mediated by the ER (endoplasmic reticulum) stress-sensor proteins PERK [PKR (double-stranded RNA-activated protein kinase)-like ER kinase], IRE1 (inositol-requiring kinase 1) and ATF6 (activating transcription factor 6). The present study shows that ASNS (asparagine synthetase) transcription activity was up-regulated in HepG2 cells treated with the UPR activators thapsigargin and tunicamycin. ChIP (chromatin immunoprecipitation) analysis demonstrated that during ER stress, ATF4, ATF3 and C/EBPβ (CCAAT/enhancer-binding protein β) bind to the ASNS proximal promoter region that includes the genomic sequences NSRE (nutrient-sensing response element)-1 and NSRE-2, previously implicated by mutagenesis in UPR activation. Consistent with increased ASNS transcription, ChIP analysis also demonstrated that UPR signalling resulted in enhanced recruitment of general transcription factors, including RNA Pol II (polymerase II), to the ASNS promoter. The ASNS gene is also activated by the AAR (amino acid response) pathway following amino acid deprivation of tissue or cells. Immunoblot analysis of HepG2 cells demonstrated that simultaneous activation of the AAR and UPR pathways did not further increase the ASNS or ATF4 protein abundance when compared with triggering either pathway alone. In addition, siRNA (small interfering RNA)-mediated knockdown of XBP1 (X-box-binding protein 1), ATF6α or ATF6β expression did not affect ASNS transcription, whereas siRNA against ATF4 suppressed ASNS transcription during UPR activation. Collectively, these results indicate that the PERK/p-eIF2α (phosphorylated eukaryotic initiation factor 2α)/ATF4 signalling cascade is the only arm of the UPR that is responsible for ASNS transcriptional induction during ER stress. Consequently, ASNS NSRE-1 and NSRE-2, in addition to ERSE (ER stress response element)-I, ERSE-II and the mUPRE (mammalian UPR element), function as mammalian ER-stress-responsive sequences.

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Jin, Byungseok, Tokiro Ishikawa, Makoto Kashima, Rei Komura, Hiromi Hirata, Tetsuya Okada, and Kazutoshi Mori. "Activation of XBP1 but not ATF6α rescues heart failure induced by persistent ER stress in medaka fish." Life Science Alliance 6, no. 7 (May 9, 2023): e202201771. http://dx.doi.org/10.26508/lsa.202201771.

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The unfolded protein response is triggered in vertebrates by ubiquitously expressed IRE1α/β (although IRE1β is gut-specific in mice), PERK, and ATF6α/β, transmembrane-type sensor proteins in the ER, to cope with ER stress, the accumulation of unfolded and misfolded proteins in the ER. Here, we burdened medaka fish, a vertebrate model organism, with ER stress persistently from fertilization by knocking out theAXERgene encoding an ATP/ADP exchanger in the ER membrane, leading to decreased ATP concentration–mediated impairment of the activity of Hsp70- and Hsp90-type molecular chaperones in the ER lumen. ER stress and apoptosis were evoked from 4 and 6 dpf, respectively, leading to the death of allAXER-KO medaka by 12 dpf because of heart failure (medaka hatch at 7 dpf). Importantly, constitutive activation of IRE1α signaling—but not ATF6α signaling—rescued this heart failure and allowedAXER-KO medaka to survive 3 d longer, likely because of XBP1-mediated transcriptional induction of ER-associated degradation components. Thus, activation of a specific pathway of the unfolded protein response can cure defects in a particular organ.

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Thuerauf, Donna J., Marie Marcinko, Peter J. Belmont, and Christopher C. Glembotski. "Effects of the Isoform-specific Characteristics of ATF6α and ATF6β on Endoplasmic Reticulum Stress Response Gene Expression and Cell Viability." Journal of Biological Chemistry 282, no. 31 (May 23, 2007): 22865–78. http://dx.doi.org/10.1074/jbc.m701213200.

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Druelle, Clémentine, Claire Drullion, Julie Deslé, Nathalie Martin, Laure Saas, Johanna Cormenier, Nicolas Malaquin, et al. "ATF6α regulates morphological changes associated with senescence in human fibroblasts." Oncotarget 7, no. 42 (August 22, 2016): 67699–715. http://dx.doi.org/10.18632/oncotarget.11505.

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Kezuka, Dai, Mika Tkarada-Iemata, Tsuyoshi Hattori, Kazutoshi Mori, Ryosuke Takahashi, Yasuko Kitao, and Osamu Hori. "Deletion of Atf6α enhances kainate-induced neuronal death in mice." Neurochemistry International 92 (January 2016): 67–74. http://dx.doi.org/10.1016/j.neuint.2015.12.009.

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Sharma, Rohit B., Jarin T. Snyder, and Laura C. Alonso. "Atf6α impacts cell number by influencing survival, death and proliferation." Molecular Metabolism 27 (September 2019): S69—S80. http://dx.doi.org/10.1016/j.molmet.2019.06.005.

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Xue, Fei, Harmeet Malhi, Vijay Shah, and Jessica L. Maiers. "Su1691 ATF6α SIGNALING IS CRUCIAL FOR HSC ACTIVATION AND FIBROGENESIS." Gastroenterology 158, no. 6 (May 2020): S—1383—S—1384. http://dx.doi.org/10.1016/s0016-5085(20)34126-3.

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Kim, Hee Suk, Yongjin Kim, Min Jae Lim, Yun-Gyu Park, Serk In Park, and Jeongwon Sohn. "The p38‐activated ER stress‐ATF6α axis mediates cellular senescence." FASEB Journal 33, no. 2 (September 27, 2018): 2422–34. http://dx.doi.org/10.1096/fj.201800836r.

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Baumeister, Peter, Shengzhan Luo, William C. Skarnes, Guangchao Sui, Edward Seto, Yang Shi, and Amy S. Lee. "Endoplasmic Reticulum Stress Induction of the Grp78/BiP Promoter: Activating Mechanisms Mediated by YY1 and Its Interactive Chromatin Modifiers." Molecular and Cellular Biology 25, no. 11 (June 1, 2005): 4529–40. http://dx.doi.org/10.1128/mcb.25.11.4529-4540.2005.

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ABSTRACT The unfolded protein response is an evolutionarily conserved mechanism whereby cells respond to stress conditions that target the endoplasmic reticulum (ER). The transcriptional activation of the promoter of GRP78/BiP, a prosurvival ER chaperone, has been used extensively as an indicator of the onset of the UPR. YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions. Previously, in vivo footprinting analysis revealed that the YY1 binding site of the ER stress response element of the Grp78 promoter exhibits ER stress-induced changes in occupancy. Toward understanding the underlying mechanisms of these unique phenomena, we performed chromatin immunoprecipitation analyses, revealing that YY1 only occupies the Grp78 promoter upon ER stress and is mediated in part by the nuclear form of ATF6. We show that YY1 is an essential coactivator of ATF6 and uncover their specific interactive domains. Using small interfering RNA against YY1 and insertional mutation of the gene encoding ATF6α, we provide direct evidence that YY1 and ATF6 are required for optimal stress induction of Grp78. We also discovered enhancement of the ER-stressed induction of the Grp78 promoter through the interaction of YY1 with the arginine methyltransferase PRMT1 and evidence of its action through methylation of the arginine 3 residue on histone H4. Furthermore, we detected ER stress-induced binding of the histone acetyltransferase p300 to the Grp78 promoter and histone H4 acetylation. A model for the ER stress-mediated transcription factor binding and chromatin modifications at the Grp78 promoter leading to its activation is proposed.

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Potes, Yaiza, Beatriz De Luxán-Delgado, Adrian Rubio-González, Russel J. Reiter, and Ana Maria Coto Montes. "Dose-dependent beneficial effect of melatonin on obesity; interaction of melatonin and leptin." Melatonin Research 2, no. 1 (February 28, 2019): 1–8. http://dx.doi.org/10.32794/mr11250008.

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Although numerous studies have noted leptin’s role in obesity, there are still important mechanisms insights that need to be elucidated. Disturbed leptin production is associated with eating disorders, leading to alter food intake and energy expenditure. Proper regulation of protein homeostasis is critical for metabolic diseases such as obesity. Thus, the purpose of the present work was to study the unfolded protein response, which is implicated in the alleviation of endoplasmic reticulum stress-dependent dysregulation of nutritional status. We studied the effect of leptin deficiency on liver, brain and skeletal muscle tissues in obese (ob/ob) mice and the actions of a daily melatonin administration, as a possible treatment. Our findings showed that the leptin-deficient mice presented tissue-specific alterations of the three adaptive unfolded protein responses. ATF6α arm is strongly activated in all of them, indicating a deregulated lipid metabolism by the lack of leptin. Likewise, melatonin also alleviates unfolded protein response in a tissue-specific manner, acting mainly in the restoration of this disturbed ATF6α pathway. These findings support the use of melatonin as a potential therapeutic treatment against leptin-associated disorders.

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Akai, Ryoko, Hisayo Hamashima, Michiko Saito, Kenji Kohno, and Takao Iwawaki. "Partial limitation of cellular functions and compensatory modulation of unfolded protein response pathways caused by double-knockout of ATF6α and ATF6β." Cell Stress and Chaperones 29, no. 1 (February 2024): 34–48. http://dx.doi.org/10.1016/j.cstres.2023.11.002.

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Meco, Giuseppe. "The role of ATF6α in protecting dopaminergic neurons form MPTP toxicity." Movement Disorders 26, no. 3 (February 15, 2011): 378. http://dx.doi.org/10.1002/mds.23636.

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Peng, Chiung-Chi, Chang-Rong Chen, Chang-Yu Chen, Yen-Chung Lin, Kuan-Chou Chen, and Robert Y. Peng. "Nifedipine Upregulates ATF6-α, Caspases -12, -3, and -7 Implicating Lipotoxicity-Associated Renal ER Stress." International Journal of Molecular Sciences 21, no. 9 (April 29, 2020): 3147. http://dx.doi.org/10.3390/ijms21093147.

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Nifedipine (NF) is reported to have many beneficial effects in antihypertensive therapy. Recently, we found that NF induced lipid accumulation in renal tubular cells. Palmitic acid-induced renal lipotoxicity was found to be partially mediated by endoplasmic reticular (ER) stress, while it can also be elicited by NF in kidney cells; we examined the induction of suspected pathways in both in vitro and in vivo models. NRK52E cells cultured in high-glucose medium were treated with NF (30 µM) for 24–48 h. ER stress-induced lipotoxicity was explored by staining with thioflavin T and Nile red, transmission electron microscopy, terminal uridine nick-end labeling, and Western blotting. ER stress was also investigated in rats with induced chronic kidney disease (CKD) fed NF for four weeks. NF induced the production of unfolded protein aggregates, resulting in ER stress, as evidenced by the upregulation of glucose-regulated protein, 78 kDa (GRP78), activating transcription factor 6α (ATF6α), C/EBP-homologous protein (CHOP), and caspases-12, -3, and -7. In vitro early apoptosis was more predominant than late apoptosis. Most importantly, ATF6α was confirmed to play a unique role in NF-induced ER stress in both models. CKD patients with hypertension should not undergo NF therapy. In cases where it is required, alleviation of ER stress should be considered to avoid further damaging the kidneys.

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Egawa, Naohiro, Keisuke Yamamoto, Haruhisa Inoue, Rie Hikawa, Katsunori Nishi, Kazutoshi Mori, and Ryosuke Takahashi. "The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death." Journal of Biological Chemistry 286, no. 10 (December 3, 2010): 7947–57. http://dx.doi.org/10.1074/jbc.m110.156430.

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Lu, Wenjun, Daisuke Hagiwara, Yoshiaki Morishita, Masayoshi Tochiya, Yoshinori Azuma, Hidetaka Suga, Motomitsu Goto, et al. "Unfolded protein response in hypothalamic cultures of wild-type and ATF6α-knockout mice." Neuroscience Letters 612 (January 2016): 199–203. http://dx.doi.org/10.1016/j.neulet.2015.12.031.

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Egawa, Naohiro, Keisuke Yamamoto, Haruhisa Inoue, Katsunori Nishi, Kazutoshi Mori, and Ryosuke Takahashi. "The role of ER stress sensor ATF6α in the pathogenesis of Parkinson's disease." Neuroscience Research 65 (January 2009): S118. http://dx.doi.org/10.1016/j.neures.2009.09.554.

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Soczewski, E., S. Gori, D. Paparini, E. Grasso, L. Fernández, L. Gallino, A. Schafir, et al. "VIP conditions human endometrial receptivity by privileging endoplasmic reticulum stress through ATF6α pathway." Molecular and Cellular Endocrinology 516 (October 2020): 110948. http://dx.doi.org/10.1016/j.mce.2020.110948.

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Unno, Hirotoshi, Marina Miller, Peter Rosenthal, Andrew Beppu, Sudipta Das, and David H. Broide. "Activating transcription factor 6α (ATF6α) regulates airway hyperreactivity, smooth muscle proliferation, and contractility." Journal of Allergy and Clinical Immunology 141, no. 1 (January 2018): 439–42. http://dx.doi.org/10.1016/j.jaci.2017.07.053.

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Wu, Jun, D. Thomas Rutkowski, Meghan Dubois, Jayanth Swathirajan, Thomas Saunders, Junying Wang, Benbo Song, Grace D. Y. Yau, and Randal J. Kaufman. "ATF6α Optimizes Long-Term Endoplasmic Reticulum Function to Protect Cells from Chronic Stress." Developmental Cell 13, no. 3 (September 2007): 351–64. http://dx.doi.org/10.1016/j.devcel.2007.07.005.

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Lowe, C. E., R. J. Dennis, U. Obi, S. O'Rahilly, and J. J. Rochford. "Investigating the involvement of the ATF6α pathway of the unfolded protein response in adipogenesis." International Journal of Obesity 36, no. 9 (November 29, 2011): 1248–51. http://dx.doi.org/10.1038/ijo.2011.233.

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Fernandez-Fernandez, Maria Rosario, Isidro Ferrer, and Jose J. Lucas. "Impaired ATF6α processing, decreased Rheb and neuronal cell cycle re-entry in Huntington's disease." Neurobiology of Disease 41, no. 1 (January 2011): 23–32. http://dx.doi.org/10.1016/j.nbd.2010.08.014.

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Yarapureddy, Suma, Jazmine Abril, Janet Foote, Saravana Kumar, Omar Asad, Veena Sharath, Janine Faraj, et al. "ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma." Neoplasia 21, no. 6 (June 2019): 516–32. http://dx.doi.org/10.1016/j.neo.2019.02.004.

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Wan, Yan-Jun, Yan-Hang Wang, Qiang Guo, Yong Jiang, Peng-Fei Tu, and Ke-Wu Zeng. "Protocatechualdehyde protects oxygen-glucose deprivation/reoxygenation-induced myocardial injury via inhibiting PERK/ATF6α/IRE1α pathway." European Journal of Pharmacology 891 (January 2021): 173723. http://dx.doi.org/10.1016/j.ejphar.2020.173723.

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