scholarly journals Mammalian Transcription Factor ATF6 Is Synthesized as a Transmembrane Protein and Activated by Proteolysis in Response to Endoplasmic Reticulum Stress

1999 ◽  
Vol 10 (11) ◽  
pp. 3787-3799 ◽  
Author(s):  
Kyosuke Haze ◽  
Hiderou Yoshida ◽  
Hideki Yanagi ◽  
Takashi Yura ◽  
Kazutoshi Mori
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Leucine Zipper ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cholesterol Homeostasis ◽  
Basic Leucine Zipper ◽  
Transmembrane Glycoprotein ◽  
Stressed Cells ◽  
The Unfolded Protein Response

The unfolded protein response (UPR) controls the levels of molecular chaperones and enzymes involved in protein folding in the endoplasmic reticulum (ER). We recently isolated ATF6 as a candidate for mammalian UPR-specific transcription factor. We report here that ATF6 constitutively expressed as a 90-kDa protein (p90ATF6) is directly converted to a 50-kDa protein (p50ATF6) in ER-stressed cells. Furthermore, we showed that the most important consequence of this conversion was altered subcellular localization; p90ATF6 is embedded in the ER, whereas p50ATF6 is a nuclear protein. p90ATF6 is a type II transmembrane glycoprotein with a hydrophobic stretch in the middle of the molecule. Thus, the N-terminal half containing a basic leucine zipper motif is oriented facing the cytoplasm. Full-length ATF6 as well as its C-terminal deletion mutant carrying the transmembrane domain is localized in the ER when transfected. In contrast, mutant ATF6 representing the cytoplasmic region translocates into the nucleus and activates transcription of the endogenous GRP78/BiP gene. We propose that ER stress-induced proteolysis of membrane-bound p90ATF6 releases soluble p50ATF6, leading to induced transcription in the nucleus. Unlike yeast UPR, mammalian UPR appears to use a system similar to that reported for cholesterol homeostasis.

scholarly journals Divest Yourself of a Preconceived Idea: Transcription Factor ATF6 Is Not a Soluble Protein!

2010 ◽  
Vol 21 (9) ◽  
pp. 1435-1438 ◽  
Author(s):  
Kazutoshi Mori
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Leucine Zipper ◽  
Transmembrane Protein ◽  
Basic Leucine Zipper ◽  
Induction Program ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

The unfolded protein response (UPR), an evolutionarily conserved transcriptional induction program that is coupled with intracellular signaling from the endoplasmic reticulum (ER) to the nucleus, is activated to cope with ER stress and to maintain the homeostasis of the ER. In 1996, we isolated a basic leucine zipper protein, which had been previously named activating transcription factor (ATF)6, as a candidate transcription factor responsible for the mammalian UPR. Subsequent analysis, however, was confounding. The problem was eventually tracked down to an unusual property of ATF6: rather than being a soluble nuclear protein, as expected for an active transcription factor, ATF6 was instead synthesized as a transmembrane protein embedded in the ER, which was activated by ER stress-induced proteolysis. ATF6 was thus unique: an ER stress sensor/transducer that is involved in all steps of the UPR, from the sensing step in the ER to the transcriptional activation step in the nucleus.

scholarly journals A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1

2004 ◽  
Vol 167 (3) ◽  
pp. 445-456 ◽  
Author(s):  
Yukio Kimata ◽  
Daisuke Oikawa ◽  
Yusuke Shimizu ◽  
Yuki Ishiwata-Kimata ◽  
Kenji Kohno
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Binding Site ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Sensory System ◽  
Type I ◽  
Stress Signal ◽  
Stress Sensing ◽  
The Unfolded Protein Response

In the unfolded protein response, the type I transmembrane protein Ire1 transmits an endoplasmic reticulum (ER) stress signal to the cytoplasm. We previously reported that under nonstressed conditions, the ER chaperone BiP binds and represses Ire1. It is still unclear how this event contributes to the overall regulation of Ire1. The present Ire1 mutation study shows that the luminal domain possesses two subregions that seem indispensable for activity. The BiP-binding site was assigned not to these subregions, but to a region neighboring the transmembrane domain. Phenotypic comparison of several Ire1 mutants carrying deletions in the indispensable subregions suggests these subregions are responsible for multiple events that are prerequisites for activation of the overall Ire1 proteins. Unexpectedly, deletion of the BiP-binding site rendered Ire1 unaltered in ER stress inducibility, but hypersensitive to ethanol and high temperature. We conclude that in the ER stress-sensory system BiP is not the principal determinant of Ire1 activity, but an adjustor for sensitivity to various stresses.

scholarly journals Combined irradiation by gamma rays and carbon nuclei increases the C/EBP-β LIP-isoform content in the pituitary gland of rats

2019 ◽  
Vol 488 (1) ◽  
pp. 108-111
Author(s):  
I. P. Anokhina ◽  
P. K. Anokhin ◽  
V. S. Kokhan
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Ionizing Radiation ◽  
Pituitary Gland ◽  
Gamma Rays ◽  
Wistar Rats ◽  
Leucine Zipper ◽  
Inflammatory Responses ◽  
Endoplasmic Reticulum Stress Response ◽  
Basic Leucine Zipper

C/EBP-β, a basic leucine zipper transcription factor, has important roles in the regulation of organism’s immune and inflammatory responses. Wistar rats subjected to the combined irradiation were characterized by an increase in the content of C/EBP-β LIP-isoform in the pituitary gland. The obtained data indicate that moderate doses of ionizing radiation to initiate the endoplasmic reticulum stress response and are likely to initiate C/EBP-β-mediated cell death according to the apoptotic scenario. This study also confirms the earlier hypothesis about the alterations of the hypothalamic-pituitary-adrenocortical axis in response to moderate doses of ionizing radiation.

scholarly journals An essential dimer-forming subregion of the endoplasmic reticulum stress sensor Ire1

2005 ◽  
Vol 391 (1) ◽  
pp. 135-142 ◽  
Author(s):  
Daisuke Oikawa ◽  
Yukio Kimata ◽  
Masato Takeuchi ◽  
Kenji Kohno
Keyword(s):  
Endoplasmic Reticulum ◽  
Recombinant Protein ◽  
Endoplasmic Reticulum Stress ◽  
Transmembrane Protein ◽  
Type I ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Recombinant Fragments ◽  
Made In

The luminal domain of the type I transmembrane protein Ire1 senses endoplasmic reticulum stress by an undefined mechanism to up-regulate the signalling pathway for the unfolded protein response. Previously, we proposed that the luminal domain of yeast Ire1 is divided into five subregions, termed subregions I–V sequentially from the N-terminus. Ire1 lost activity when internal deletions of subregion II or IV were made. In the present paper, we show that partial proteolysis of a recombinant protein consisting of the Ire1 luminal domain suggests that subregions II–IV are tightly folded. We also show that a recombinant protein of subregions II–IV formed homodimers, and that this homodimer formation was impaired by an internal deletion of subregion IV. Furthermore, recombinant fragments of subregion IV exhibited a self-binding ability. Therefore, although its sequence is little conserved evolutionarily, subregion IV plays an essential role to promote Ire1 dimer formation.

scholarly journals Induction of metallothionein I by phenolic antioxidants requires metal-activated transcription factor 1 (MTF-1) and zinc

2004 ◽  
Vol 380 (3) ◽  
pp. 695-703 ◽  
Author(s):  
Yongyi BI ◽  
Richard D. PALMITER ◽  
Kristi M. WOOD ◽  
Qiang MA
Keyword(s):  
Transcription Factor ◽  
Phase Ii ◽  
Leucine Zipper ◽  
Gene Promoter ◽  
Phenolic Antioxidants ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Free Zinc ◽  
Genes Encoding ◽  
Transcription Factor 1

Phenolic antioxidants, such as tBHQ [2,5-di-(t-butyl)-1,4-hydroquinone], induce Mt1 (metallothionein 1) gene expression and accumulation of MT protein. Induction of Mt1 mRNA does not depend on protein synthesis, and correlates with oxidation–reduction functions of the antioxidants. In the present study, we analysed the biochemical pathway of the induction. Induction depends on the presence of MTF-1 (metal-activated transcription factor 1), a transcription factor that is required for metal-induced transcription of Mt1, but does not require nuclear factor erythroid 2-related factor 2, a tBHQ-activated CNC bZip (cap ‘n’ collar basic leucine zipper) protein, that is responsible for regulating genes encoding phase II drug-metabolizing enzymes. Moreover, tBHQ induces the expression of MRE-βGeo, a reporter gene driven by five metal response elements that constitute an optimal MTF-1 binding site. Reconstitution of Mtf1-null cells with MTF-1 restores induction by both zinc and tBHQ. Unlike activation of phase II genes by tBHQ, induction of Mt1 expression does not occur in the presence of EDTA, when cells are cultured in zinc-depleted medium, or in cells with reduced intracellular ‘free’ zinc due to overexpression of ZnT1, a zinc-efflux transporter, indicating that induction requires zinc. In addition, fluorescence imaging reveals that tBHQ increases cytoplasmic free zinc concentration by mobilizing intracellular zinc pools. These findings establish that phenolic antioxidants activate Mt1 transcription by a zinc-dependent mechanism, which involves MTF-1 binding to metal regulator elements in the Mt1 gene promoter.

Basic leucine zipper transcription factor OsbZIP16 positively regulates drought resistance in rice

Plant Science ◽  
2012 ◽  
Vol 193-194 ◽  
pp. 8-17 ◽  
Author(s):  
Hao Chen ◽  
Wei Chen ◽  
Junli Zhou ◽  
Hang He ◽  
Liangbi Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Drought Resistance ◽  
Leucine Zipper ◽  
Basic Leucine Zipper
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