2001 Fiscal Year Final Research Report Summary
Analysis of the UPR, a transcriptional induction process coupled with intracellular signaling from the endoplasmic reticulum to the nucleus
| Project/Area Number |
12680692
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
MORI Kazutoshi Kyoto University, Graduate School of Biostudies, Associate professor, 大学院・生命科学研究科, 助教授 (70182194)
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| Project Period (FY) |
2000 – 2001
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| Keywords | endoplasmic reticulum / molecular chaperone / folding enzymes / intracellular signaling / transcriptional induction / transcription factor / proteolysis / nuclear translocation |
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| Research Abstract |
By 1999, we showed that the human basic leucine zipper protein ATF6 we isolated as a transcription factor specific to the mammalian UPR is constitutively synthesized as a type II transmembrane glycoprotein localized in the endoplasmic reticulum (ER) and activated by proteolysis in response to ER stress. From 2000 to 2001, we further analyzed various properties of ATF6 in more detail and obtained the following results.
(1) The N-terminal fragment of ATF6 relocates from the ER to the nucleus upon ER stress-induced proteolysis (visualized by indirect immunofluorescence analysis). (2) The consensus sequence of the cis-acting ER stress response element (ERSE) necessary and sufficient for the mammalian UPR is CCAAT-N9-CCACG. Although ATF6 cannot bind to ERSE by itself, ATF6 can bind to the CCACG part of ERSE when the CCAAT part is bound to the ubiquitous transcription factor NF-Y. (3) Transcriptional activities of wild-type and various mutant ERSE-like sequences are correlated well with their abilities to bind ATF6. (4) ER stress-induced proteolysis of ATF6 and subsequent transcriptional induction of BiP/GRP78 (a major molecular chaperone in the ER) is specifically blocked by the serine protease inhibitor AEBSF at the concentration of 300 μM. (5) Comprehensive analysis of target genes of the UPR and ATF6 revealed that approximately half of UPR-target genes are directly regulated by ATF6 and that a majority of ATF6-target genes encodes molecular chaperones and folding enzymes in the ER. (6) In cells possessing Familial Alzheimer disease-linked mutation in the presenilin gene, ER stress-induced activation of ATF6 is mitigated.
Above results strongly indicate that ATF6 plays a major role in the mammalian UPR.
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