2002 Fiscal Year Final Research Report Summary
Functional analyses of ER stress sensor proteins
| Project/Area Number |
13480239
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | NARA INSTITUTE OF SCIENCE AND TECHNOLOGY |
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Principal Investigator |
KOHNO Kenji Nara Institute of Science & Technology, Research & Education Center for Genetic Information, Professor, 遺伝子教育研究センター, 教授 (50142005)
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| Co-Investigator(Kenkyū-buntansha) |
TSURU Akio NAIST, Res. & Edu. Ctr for Genet. Inf., Instructor, 遺伝子教育研究センター, 助手 (80273861)
KIMATA Ykio NAIST, Res. & Edu. Ctr for Genet. Inf., Instructor, 遺伝子教育研究センター, 助手 (60263448)
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| Project Period (FY) |
2001 – 2002
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| Keywords | ER stress / Unfolded Protein Response / IRE1 / BiP / transport vesicle |
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| Research Abstract |
1. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) induces a transcriptional response in the nucleus, leading to the upregulation of many ER-resident proteins involved in protein folding, to protect cells from ER stress. This response is called the unfolded protein response (UPR), which is essential for maintaining the ER homeostasis. Two important factors for UPR have been identified. One is an ER stress sensor protein Ire1, and the other is a transcription factor Hac1. Overexpression of IRE1 or HAC1 specifically suppressed growth defects of sec mutants defective in COPII vesicle formation. These findings suggest that the activation of the UPR affects ER-to-Golgi transport via stimulation of COPII vesicle formation from the ER.
Induction of UPR needs the activation of Ire1. It was previously hypothesized that BiP/Kar2 plays a direct role in the signaling mechanism. In this model, association of BiP/Kar2 with Ire1 represses the UPR pathway while under conditions of ER stress, BiP/Kar2 dissociation leads to activation. To test this model, we analyzed five temperature-sensitive alleles of the yeast KAR2 gene. When cells carrying a mutation in the Kar2 substrate-binding domain were incubated at the restrictive temperature, association of Kar2 to Ire1 was disrupted, and the UPR pathway was activated even in the absence of extrinsic ER stress. Conversely, cells carrying a mutation in the Kar2 ATPase domain, in which Kar2 poorly dissociated from Ire1 even in the presence of tunicamycin, a potent inducer of ER stress, were unable to activate the pathway. Our findings provide strong evidence in support of BiP/Kar2-dependent Ire1 regulation model and suggest that Ire1 associate with Kar2 as a chaperone substrate.
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