| Project/Area Number |
14037233
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyoto University |
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Principal Investigator |
MORI Kazutoshi Kyoto University, Kyoto University, Graduate School of Science, Professor (70182194)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥85,000,000 (Direct Cost: ¥85,000,000)
Fiscal Year 2006: ¥19,000,000 (Direct Cost: ¥19,000,000)
Fiscal Year 2005: ¥19,000,000 (Direct Cost: ¥19,000,000)
Fiscal Year 2004: ¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2003: ¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2002: ¥19,000,000 (Direct Cost: ¥19,000,000)
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| Keywords | molecular chaperone / endoplasmic reticulum / folding / degradation / transcriptional induction / protease / mRNA splicing / quality control / 変異株 / 膜タンパク質 / マイクロアレイ解析 / 転写因子 / 酵素 / 巻き戻し / 核 / ゴルジ装置 / 情報伝達 / 細胞内輸送 / プロテアーゼ阻害剤 / タンパクの品質管理 / フォールディング / ユビキチン / プロテアソーム |
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| Research Abstract |
The endoplamic reticulum (ER) is the place for folding and quality control of newly synthesized secretory and transmembrane proteins. When unfolded proteins are accumulated in the ER under ER stress conditions, the unfolded protein response (UPR), a transcriptional induction program coupled with intracellular signaling from the ER to the nucleus, is activated to maintain the homeostasis of the ER. We have shown that the ATF6 and IRE1-XBP1 pathways play important roles in mammalian UPR. ATF6 is an ER membrane-bound transcription factor activated by proteolysis. On the other hand, XBP1 is a transcription factor whose mRNA is spliced by IRE1. Base on the difference in activation time course and the difference in DNA binding specificity between ATF6 and XBP1, we proposed a time-dependent phase shift in the mammalian UPR, that is shifted from the first phase dealt with endogenous ER chaperones (refolding only), to the second phase dealt with ER chaperones induced by the ATF6 pathway(refolding only), and to the third phase dealt with ER chaperones and ERAD components induced by the IRE1-XBP1 pathway (refolding plus degradation), depending on quality or quantity of unfolded proteins accumulated in the ER.
The ER is expanded in professional secretory cells such as plasma cells which is specialized for synthesis and secretion of antibody. We found that overexpression of XBP1 stimulates synthesis of phosphatidylcholine and phosphatidylethanolamine, major components of the ER membrane, and indicated that XBP1 is a key factor connecting quality control of proteins with organelle biogenesis.
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