scholarly journals Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases

Glia ◽  
2018 ◽  
Vol 66 (7) ◽  
pp. 1331-1345 ◽  
Author(s):  
Sarrabeth Stone ◽  
Shuangchan Wu ◽  
Stephanie Jamison ◽  
Wilaiwan Durose ◽  
Jean Pierre Pallais ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Demyelinating Diseases ◽  
Immune Mediated ◽  
Activating Transcription Factor ◽  
Activating Transcription Factor 6Α ◽  
Myelin Damage

scholarly journals ER stress signaling has an activating transcription factor 6α (ATF6)-dependent “off-switch”

2018 ◽  
Vol 293 (47) ◽  
pp. 18270-18284 ◽  
Author(s):  
Franziska Walter ◽  
Aisling O'Brien ◽  
Caoimhín G. Concannon ◽  
Heiko Düssmann ◽  
Jochen H. M. Prehn
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Neuroblastoma Cells ◽  
Stress Signaling ◽  
Signaling Proteins ◽  
Protein Levels ◽  
Activating Transcription Factor ◽  
Screening Platform ◽  
The Unfolded Protein Response ◽  
Activating Transcription Factor 6Α

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.”

scholarly journals Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 602 ◽  
Author(s):  
Erik A. Blackwood ◽  
Alina S. Bilal ◽  
Winston T. Stauffer ◽  
Adrian Arrieta ◽  
Christopher C. Glembotski
Keyword(s):  
Transcription Factor ◽  
Protein Folding ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Genetic Alterations ◽  
Hypertrophic Growth ◽  
Specific Manner ◽  
Activating Transcription Factor ◽  
Activating Transcription Factor 6Α ◽  
Unique Ability

The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac myocytes growing in size. Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e., proteostasis). This increase in the protein folding demand in the growing cardiac myocyte activates the transcription factor, ATF6 (activating transcription factor 6α, an inducer of genes that restore proteostasis. Previously, ATF6 has been shown to induce ER-targeted proteins functioning primarily to enhance ER protein folding and degradation. More recent studies, however, have illuminated adaptive roles for ATF6 functioning outside of the ER by inducing non-canonical targets in a stimulus-specific manner. This unique ability of ATF6 to act as an initial adaptive responder has bolstered an enthusiasm for identifying small molecule activators of ATF6 and similar proteostasis-based therapeutics.

scholarly journals Activating Transcription Factor 6α Is Required for the Vasopressin Neuron System to Maintain Water Balance Under Dehydration in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (12) ◽  
pp. 4905-4914 ◽  
Author(s):  
Yoshinori Azuma ◽  
Daisuke Hagiwara ◽  
Wenjun Lu ◽  
Yoshiaki Morishita ◽  
Hidetaka Suga ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Water Balance ◽  
Urine Volume ◽  
Neuronal Loss ◽  
Electron Microscopic ◽  
Neuron System ◽  
Access To Water ◽  
Activating Transcription Factor ◽  
Vasopressin Neuron ◽  
Activating Transcription Factor 6Α

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.

scholarly journals 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

2020 ◽  
Vol 21 (3) ◽  
pp. 1134 ◽  
Author(s):  
Winston T. Stauffer ◽  
Adrian Arrieta ◽  
Erik A. Blackwood ◽  
Christopher C. Glembotski
Keyword(s):  
Transcription Factor ◽  
Protein Folding ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Fine Tuning ◽  
Cellular Functions ◽  
Similar Mode ◽  
Activating Transcription Factor ◽  
Activating Transcription Factor 6Α

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.

Sign in / Sign up

Export Citation Format

Share Document